SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age
Open accessAbstract
L1 retrotransposons are an abundant class of transposable elements that pose a threat to genome stability and may have a role in age-related pathologies such as cancer. Recent evidence indicates that L1s become more active in somatic tissues during the course of ageing; however the mechanisms underlying this phenomenon remain unknown. Here we report that the longevity regulating protein, SIRT6, is a powerful repressor of L1 activity. Specifically, SIRT6 binds to the 5'-UTR of L1 loci, where it mono-ADP ribosylates the nuclear corepressor protein, KAP1, and facilitates KAP1 interaction with the heterochromatin factor, HP1α, thereby contributing to the packaging of L1 elements into transcriptionally repressive heterochromatin. During the course of ageing, and also in response to DNA damage, however, we find that SIRT6 is depleted from L1 loci, allowing the activation of these previously silenced retroelements.
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Claims the paper makes
47 of 59 cited sources checked · 30 supported · 0 flagged · accuracy not yet measured
- Findingown data
L1 5′UTR sequences are heavily represented in the SIRT6 ChIP-seq dataset.
“We observed that L1 5′UTR sequences were heavily represented in the SIRT6 ChIP-seq dataset (Supplementary Fig. 5).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [28] Ram, O. et al. Combinatorial patterning of chromatin regulators uncovered by genome-wide location analysis in human cells. Cell 147, 1628–1639 (2011). source
The Results section (‘A compendium of genome-wide CR maps’; page unavailable) establishes that the paper generated chromatin-regulator ChIP-seq datasets, including SIRT6 data discussed elsewhere in the Results. But the passages in our copy do not report that L1 5′UTR sequences are heavily represented; searches for that phrase and for LINE-1 enrichment found no such result. (LLM, conf=0.83)
Experimental — accuracy not yet measured
- Findingcitation
SIRT6 co-occupies approximately 10% of KAP1-bound promoters.
“analysis of promoter arrays41,42 showed that SIRT6 only co-occupies approximately 10% of KAP1 bound promoters”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [41] Li, X. et al. Role for KAP1 serine 824 phosphorylation and sumoylation/desumoylation switch in regulating KAP1-mediated transcriptional repression. J. Biol. Chem. 282, 36177–36189 (2007). source
The introduction describes KAP1 as a transcriptional corepressor, and the Discussion examines its phosphorylation and desumoylation. Searches for SIRT6, promoter-array co-occupancy, and the approximately 10% figure found no passage addressing the claimed overlap. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites [42] White, D. et al. The ATM substrate KAP1 controls DNA repair in heterochromatin: regulation by HP1 proteins and serine 473/824 phosphorylation. Mol. Cancer Res. 10, 401–414 (2012). source
The Results passages discuss KAP1 with HP1 at a transgene array and KAP1 phosphorylation after DNA damage, not promoter occupancy. Searches for SIRT6, promoter arrays, and the approximately 10% overlap found no passage in our copy addressing the claim. (LLM, conf=0.75)
Experimental — accuracy not yet measured
- Premisecitation
DNA damage is more abundant in old cells and tissues.
“DNA damage is more abundant in old cells and tissues37,38.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [37] Hoeijmakers, J. H. DNA damage, aging, and cancer. N. Engl. J. Med. 361, 1475–1485 (2009). source
- cites [38] Vijg, J. Aging genomes: a necessary evil in the logic of life. Bioessays (2014). source
In “DNA damage is abundant, but does it cause aging?” (page unavailable), Vijg reports age-related increases in some forms of DNA damage in animal cells and tissues, but says the results are often conflicting. The section also reports increases in double-strand-break markers in aging mouse tissues and in breaks in human and mouse oocytes. These findings support the general direction of the claim, but not its unqualified assertion about DNA damage in old cells and tissues. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
L1s become more transcriptionally active during aging and senescence.
“this study builds on the mounting body of evidence which suggests that L1s become more transcriptionally active during aging and senescence10,49”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [10] De Cecco, M. et al. Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging Cell 12, 247–256 (2013). source
The Results report increased L1 RNA expression in replicatively senescent cells (Fig. 3C), supporting the senescence portion of the claim. The Discussion links aging to changes that could permit transposable-element expression, but does not report increased L1 transcription during organismal aging. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [49] De Cecco, M. et al. Transposable elements become active and mobile in the genomes of aging mammalian somatic tissues. Aging (Albany NY) 5, 867–883 (2013). source
- Premisecitation
SIRT6 is a chromatin-associated protein.
“Because SIRT6 is a chromatin-associated protein26”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [26] Michishita, E., Park, J. Y., Burneskis, J. M., Barrett, J. C. & Horikawa, I. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol. Biol. Cell. 16, 4623–4635 (2005). source
- Premisecitation
Overexpression of exogenous full length L1 induces a senescence-like phenotype in human fibroblasts and adult stem cells.
“overexpression of exogenous full length L1 has been shown to induce a senescence-like phenotype in human fibroblasts and adult stem cells9.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [9] Belancio, V. P., Roy-Engel, A. M., Pochampally, R. R. & Deininger, P. Somatic expression of LINE-1 elements in human tissues. Nucleic Acids Res. 38, 3909–3922 (2010). source
- Premisecitation
SIRT6 rapidly relocalizes to DNA damage sites in response to oxidative stress.
“SIRT6 is known to rapidly relocalize to DNA damage sites in response to oxidative stress19,36.”
Quote in the paperSubstantial claim2 of 2 sources checked - Findingown data
SIRT6 facilitates KAP1 interaction with HP1α.
“facilitates KAP1 interaction with the heterochromatin factor, HP1α”
- Also stated in: § SIRT6 mono-ADP ribosylates KAP1 to promote L1 silencing · boosted
“in the WT SIRT6 and the SIRT6 R65A, but not SIRT6 G60A or SIRT6 S56Y, strongly stimulated binding between KAP1 and HP1α (Fig. 3f).”
Quote in the paperSubstantial claim - Also stated in: § SIRT6 mono-ADP ribosylates KAP1 to promote L1 silencing · boosted
- Findingown data
SIRT6 binds to the 5′UTR of L1 loci.
“SIRT6 binds to the 5′UTR of L1 loci”
- Also stated in: § SIRT6 regulates packaging of L1s into heterochromatin · plain
“SIRT6 was specifically enriched at the 5′UTR of L1 loci (Fig. 1g).”
Quote in the paperSubstantial claim - Also stated in: § SIRT6 regulates packaging of L1s into heterochromatin · plain
- Findingown data
SIRT6 is a powerful suppressor/repressor of L1 retrotransposon activity.
“Here we report that the longevity regulating protein, SIRT6, is a powerful repressor of L1 activity.”
- Also stated in: § Introduction · boosted
“Here we report that SIRT6 is a powerful suppressor of L1 retrotransposon activity.”
- Also stated in: § Discussion · boosted
“we have demonstrated that the longevity protein, SIRT6, is a critical suppressor of L1 activity.”
Quote in the paperSubstantial claim - Also stated in: § Introduction · boosted
- Findingown data
SIRT6 mono-ADP ribosylates KAP1.
“it mono-ADP ribosylates the nuclear corepressor protein, KAP1”
- Also stated in: § SIRT6 mono-ADP ribosylates KAP1 to promote L1 silencing · plain
“SIRT6 transferred radiolabelled NAD+ to KAP1, but not to any other substrate tested (Fig. 3b).”
Quote in the paperSubstantial claim - Also stated in: § SIRT6 mono-ADP ribosylates KAP1 to promote L1 silencing · plain
- Findingown data
In the absence of SIRT6, higher order chromatin structures are significantly perturbed.
“Micrococcal nuclease digestion of genomic DNA from WT and SIRT6 KO MEFs revealed that in the absence of SIRT6, higher order chromatin structures are significantly perturbed (Fig. 2a).”
Quote in the paperSubstantial claim - Findingown data
L1 loci are particularly sensitive to micrococcal nuclease treatment in SIRT6 KO cells.
“closer examination revealed that L1 loci were particularly sensitive to micrococcal nuclease treatment (Supplementary Fig. 6).”
Quote in the paperSubstantial claim - Findingown data
Deletion of SIRT6 results in a 3.3-fold increase in L1 retrotransposition frequency.
“Deletion of SIRT6 resulted in a 3.3-fold increase in L1 retrotransposition frequency (Fig. 1a).”
Quote in the paperSubstantial claim - Findingown data
SIRT6-mediated silencing of the L1 5′UTR is similar in efficiency to SIRT6 repression of other known SIRT6 regulated genes.
“The efficiency with which SIRT6 mediated the silencing of the L1 5′UTR was similar to the efficiency with which SIRT6 repressed other known SIRT6 regulated genes (Supplementary Fig. 4).”
Quote in the paperNot a substantial claim - Findingown data
During aging, SIRT6 is depleted from L1 loci.
“During the course of aging, and also in response to DNA damage, however, we find that SIRT6 is depleted from L1 loci”
- Also stated in: § SIRT6 vacates L1 loci during aging and in response to stress · plain
“ChIP analysis revealed that SIRT6 was depleted from the L1 5′UTR in senescent cells (Fig. 4c) and also in old brain tissue (Fig. 4d; Supplementary Fig. 16a and 16b)”
- Also stated in: § Discussion · plain
“during the course of aging, we observed that SIRT6 is depleted from L1 loci”
Quote in the paperSubstantial claim - Also stated in: § SIRT6 vacates L1 loci during aging and in response to stress · plain
- Findingown data
The CpG island within the L1 5′UTR is hypomethylated in SIRT6 KO cells.
“the CpG island within the L1 5′UTR was hypomethylated (Fig. 2b)”
Quote in the paperSubstantial claim - Findingown data
SIRT6 localizes to L1 loci in HDF cells.
“We confirmed that SIRT6 localized to L1 loci in HDF cells by ChIP”
Quote in the paperSubstantial claim - Findingown data
SIRT6 KO MEFs have elevated genomic L1 DNA content.
“SIRT6 KO MEFs had elevated genomic L1 DNA content”
Quote in the paperSubstantial claim - Findingown data
Overexpression of SIRT6 strongly represses signaling from the human L1 5′UTR luciferase reporter, both episomally and chromosomally integrated.
“Overexpression of SIRT6 strongly repressed signaling from this reporter, both in an episomal and chromosomally integrated context (Fig. 1f).”
Quote in the paperSubstantial claim- Rests on an assumption: L1 transcription is driven by an internal promoter within the L1 5′UTR.
- Findingown data
H3K9me3 is significantly depleted from the endogenous L1 5′UTR in SIRT6 KO cells.
“the constitutive heterochromatin marker, histone H3 trimethylated at Lys9, was significantly depleted from the endogenous L1 5′UTR in SIRT6 KO cells (Fig. 2c; Supplementary Fig. 7a).”
Quote in the paperSubstantial claim - Findingown data
SIRT6 interactions with KAP1, HP-1α, and MeCP2 are independent of DNA.
“these interactions were independent of DNA (Supplementary Fig. 8).”
Quote in the paperNot a substantial claim - Findingown data
SIRT6 is specifically enriched at the 5′UTR of L1 loci.
“observed that SIRT6 was specifically enriched at the 5′UTR of L1 loci (Fig. 1g).”
Quote in the paperSubstantial claim - Findingown data
SIRT6 depletion increases transcriptional activity of several other repetitive elements, including Alu elements and minor satellite repeats.
“We also observed an increase in the transcriptional activity of several other repetitive elements, including Alu elements and minor satellite repeats (Supplementary Fig. 3).”
Quote in the paperNot a substantial claim - Findingown data
Overexpression of SIRT6 in WT cells represses L1 retrotransposition frequency by 71%.
“overexpression of SIRT6 in WT cells was sufficient to repress L1 retrotransposition frequency by 71% (Fig. 1b).”
Quote in the paperSubstantial claim - Findingown data
SIRT6 interacts with multiple heterochromatin proteins, including KAP1, HP-1α, and MeCP2.
“we observed that SIRT6 interacts with multiple heterochromatin proteins, including KAP1, HP-1α (heterochromatin protein 1 alpha), and MeCP2 (Fig. 2d)”
Quote in the paperSubstantial claim - Findingown data
Depletion of SIRT6 in human dermal fibroblasts with SIRT6-targeting shRNAs results in a 4.4-fold increase in L1 expression.
“depletion of SIRT6 in human dermal fibroblasts (HDF cells) with SIRT6-targeting shRNAs resulted in a 4.4-fold increase in L1 expression (Supplementary Fig. 2).”
Quote in the paperSubstantial claim - Findingown data
L1 mRNA levels are elevated nearly five-fold in SIRT6 KO cells and tissues.
“L1 mRNA levels were elevated nearly five-fold in SIRT6 KO cells (Fig. 1c) and tissues (Fig. 1d)”
Quote in the paperSubstantial claim - Findingown data
In response to DNA damage or genotoxic stress, SIRT6 is depleted from L1 loci.
“also in response to DNA damage, however, we find that SIRT6 is depleted from L1 loci”
- Also stated in: § SIRT6 vacates L1 loci during aging and in response to stress · plain
“Treating cells with either gamma-irradiation or hydrogen peroxide induced rapid mobilization of SIRT6 away from the L1 5′UTR”
- Also stated in: § Discussion · plain
“In response to genotoxic stress, and during the course of aging, we observed that SIRT6 is depleted from L1 loci”
Quote in the paperSubstantial claim - Also stated in: § SIRT6 vacates L1 loci during aging and in response to stress · plain
- Findingown data
SIRT6 is depleted from the L1 5′UTR in senescent cells.
“ChIP analysis revealed that SIRT6 was depleted from the L1 5′UTR in senescent cells (Fig. 4c)”
Quote in the paperSubstantial claim - Findingown data
PARP1 is dispensable for SIRT6-mediated silencing of L1s.
“in our system, PARP1 was dispensable for SIRT6 mediated silencing of L1s (Supplementary Fig. 10).”
Quote in the paperNot a substantial claim - Findingown data
SIRT6 does not modulate interactions between KAP1 and SETDB1.
“we found that SIRT6 did not modulate interactions between KAP1 and SETDB1 (Supplementary Fig. 12).”
Quote in the paperSubstantial claim - Findingown data
Overexpression of SIRT6 and SIRT6 R65A restores enrichment of KAP1, HP1α, and H3K9me3 at L1 loci to wild-type levels in SIRT6 KO cells.
“overexpression of SIRT6 and SIRT6 R65A was sufficient to restore enrichment of KAP1, HP1α and H3K9me3 at L1 loci to wild type levels in SIRT6 KO cells (Supplementary Fig. 13a-c).”
Quote in the paperSubstantial claim - Findingown data
In the absence of SIRT6, the interaction between KAP1 and HP1α is strongly abrogated.
“in the absence of SIRT6, the interaction between KAP1 and HP1α was strongly abrogated (Fig. 3e).”
Quote in the paperSubstantial claim - Findingown data
Replicatively senescent human fibroblasts exhibit a 3.1-fold increase in L1 mRNA levels.
“Senescent cells, which have been implicated in the etiology of aging35, exhibited a 3.1 fold increase in L1 mRNA levels (Fig. 4a).”
Quote in the paperSubstantial claim - Findingown data
Acetylation of SIRT6 deacetylation targets H3K9ac and H3K56ac is only slightly elevated at L1 loci.
“acetylation of SIRT6 deacetylation targets, H3K9ac and H3K56ac, was only slightly elevated at L1 loci (Supplementary Figs. 9a, 9b).”
Quote in the paperSubstantial claim - Findingown data
Overexpression of KAP1 is sufficient to reduce L1 transcription by 20%.
“overexpression of KAP1 was also sufficient to reduce L1 transcription by 20% (Supplementary Fig. 11).”
Quote in the paperNot a substantial claim - Findingown data
In mice, brain tissue exhibits the most significant deregulation of L1 expression with age, with 7.1-fold increased L1 expression in old brain relative to young brain.
“the brain exhibited the most significant deregulation of L1 expression with age (7.1-fold increased L1 expression in old brain tissue, relative to young brain tissue)”
Quote in the paperSubstantial claim - Findingown data
Only the mono-ADP ribosylation activity of SIRT6 is required to abrogate the transcriptional activity of L1 elements.
“Only the mono-ADP ribosylation activity of SIRT6 was required to abrogate the transcriptional activity of L1 elements (Fig. 3a).”
Quote in the paperSubstantial claim - Findingown data
Heart tissue exhibits a non-significant decline in L1 expression with age.
“heart tissue exhibited a non-significant decline in L1 expression with age (Fig. 4b).”
Quote in the paperNot a substantial claim - Findingown data
Liver tissue exhibits a modest increase in L1 expression with age (65% increase).
“liver tissue exhibited a modest increase in L1 expression with age (65% increase)”
Quote in the paperNot a substantial claim - Findingown data
Overexpression of SIRT6 in KAP1-depleted HDF cells fails to induce L1 silencing.
“overexpression of SIRT6 in KAP1 depleted HDF cells failed to induce L1 silencing”
Quote in the paperSubstantial claim - Findingown data
SIRT6 also appears to regulate IAP expression, with IAP transcript levels elevated in SIRT6 KO cells.
“We observed that SIRT6 also appears to regulate IAP expression, with IAP transcript levels elevated in SIRT6 KO cells.”
Quote in the paperNot a substantial claim - Findingown data
Depletion of KAP1 from HDF cells by shRNA results in a 3-fold increase in L1 transcriptional activity.
“Depletion of KAP1 from HDF cells by shRNA resulted in a 3-fold increase in L1 transcriptional activity, phenocopying SIRT6 depletion (Fig. 3c)”
Quote in the paperSubstantial claim - Findingown data
In vitro, WT SIRT6 and SIRT6 R65A, but not SIRT6 G60A or SIRT6 S56Y, strongly stimulate binding between KAP1 and HP1α.
“in the WT SIRT6 and the SIRT6 R65A, but not SIRT6 G60A or SIRT6 S56Y, strongly stimulated binding between KAP1 and HP1α (Fig. 3f).”
Quote in the paperSubstantial claim - Findingown data
Treating cells with gamma-irradiation or hydrogen peroxide results in increased L1 expression.
“and resulted in increased L1 expression (Fig. 4f, Supplementary Fig. 18).”
Quote in the paperSubstantial claim - Findingown data
Overexpression of SIRT6 prior to exposure to genotoxic compounds is sufficient to prevent stress-induced activation of L1 elements.
“Overexpression of SIRT6 prior to exposure to genotoxic compounds was sufficient to prevent stress-induced activation of L1 elements (Fig. 4g).”
Quote in the paperSubstantial claim - Findingown data
SIRT6 is only slightly depleted from the L1 5′UTR in liver tissue.
“SIRT6 was only slightly depleted from the L1 5′UTR in liver tissue”
Quote in the paperNot a substantial claim - Findingown data
Treating cells with gamma-irradiation or hydrogen peroxide induces rapid mobilization of SIRT6 away from the L1 5′UTR.
“Treating cells with either gamma-irradiation or hydrogen peroxide induced rapid mobilization of SIRT6 away from the L1 5′UTR”
Quote in the paperSubstantial claim - Findingown data
SIRT6 is not significantly depleted from the L1 5′UTR in heart tissue.
“not significantly depleted from the L1 5′UTR in heart tissue (Supplementary Fig. 17)”
Quote in the paperSubstantial claim - Findingown data
Overexpression of SIRT6 in senescent cells is sufficient to partially restore L1 expression to youthful levels.
“overexpression of SIRT6 in senescent cells was sufficient to partially restore L1 expression to youthful levels (Fig. 4e).”
Quote in the paperSubstantial claim - Findingown data
SIRT6 is depleted from the L1 5′UTR in old brain tissue.
“and also in old brain tissue (Fig. 4d; Supplementary Fig. 16a and 16b)”
Quote in the paperSubstantial claim - Interpretationown data
SIRT6 contributes to packaging L1 elements into transcriptionally repressive heterochromatin.
“thereby contributing to the packaging of L1 elements into transcriptionally repressive heterochromatin.”
- Also stated in: § SIRT6 regulates packaging of L1s into heterochromatin · hedged
“Cumulatively these results indicate that SIRT6 is required for packaging L1 loci into transcriptionally repressive heterochromatin.”
- Also stated in: § Discussion · boosted
“SIRT6 enforces the silencing of L1s by coordinating the packaging of these transposable elements into transcriptionally repressive heterochromatin.”
Quote in the paperSubstantial claim - Also stated in: § SIRT6 regulates packaging of L1s into heterochromatin · hedged
- Interpretationreasoning
Depletion of SIRT6 from L1 loci allows activation or derepression of L1 retroelements.
“allowing for the activation of these previously silenced retroelements.”
- Also stated in: § Discussion · plain
“which results in upregulation of L1 activity.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Interpretationown data
Retrotransposition events occur more frequently in SIRT6 KO cells relative to WT.
“indicating that retrotransposition events occur more frequently in SIRT6 KO cells, relative to WT (Fig. 1e).”
Quote in the paperSubstantial claim - Interpretationown data
SIRT6 is required for packaging L1 loci into transcriptionally repressive heterochromatin.
“Cumulatively these results indicate that SIRT6 is required for packaging L1 loci into transcriptionally repressive heterochromatin.”
Quote in the paperSubstantial claim - Interpretationown data
KAP1 is required for SIRT6 to induce heterochromatinization of L1 loci.
“indicating that KAP1 is required for SIRT6 to induce heterochromatinization of L1 loci (Fig. 3d).”
Quote in the paperSubstantial claim - Interpretationown data
Ribosylation of KAP1 by SIRT6 is required for efficient silencing of L1 retrotransposons.
“Cumulatively, these results suggest that ribosylation of KAP1 by SIRT6 is required for efficient silencing of L1 retrotransposons.”
Quote in the paperSubstantial claim - Interpretationreasoning
The age-related increase in L1 expression can in part be explained by SIRT6 vacating L1 loci in response to stress.
“which could in part explain the age-related increase in L1 expression (Figure 5).”
Quote in the paperSubstantial claim - Interpretationown data
SIRT6 mono-ADP ribosylation of KAP1 is required for the recruitment of HP1α to L1 loci.
“we find that SIRT6 mono-ADP ribosylation of KAP1 is required for the recruitment of HP1α to L1 loci.”
Quote in the paperSubstantial claim - Interpretationreasoning
This study provides a molecular mechanism to explain the age-related increase in L1 activity.
“provides a molecular mechanism to explain this phenomenon.”
Quote in the paperSubstantial claim - Interpretationown data
Mono-ADP ribosylation of KAP1 may be critical for the suppression of transposable elements.
“Our data suggests that mono-ADP ribosylation of KAP1 may be critical for the suppression of transposable elements.”
Quote in the paperSubstantial claim - Interpretationcitation
Constitutive L1 activity can drive age-related pathologies.
“it is easy to envision how constitutive L1 activity can drive age-related pathologies.”
Quote in the paperSubstantial claim- Rests on an assumption: L1 ORF2 encodes an endonuclease that induces DNA damage when expressed.
- Rests on an assumption: Massive L1 transcriptional activity can induce mis-regulation of host gene expression and clog the host transcriptional machinery.
- Study design and conductreasoning
Normalizing raw read depth by dividing by the relative abundance of truncated L1s containing each nucleotide position provides insight into SIRT6 occupancy across only full-length L1s.
“In that way, our normalized depth provides insight into SIRT6 occupancy across only full-length L1s.”
Quote in the paperSubstantial claim- Rests on an assumption: The ratio of truncated human L1s from prior reports is applicable to the SIRT6 ChIP-seq data and cell types analyzed.
- May combine two claims. 16
- Classified as probably not a substantial claim. 39
May combine two claims.
PremisecitationKAP1 plays a critical role in suppressing endogenous retroviruses and has emerged as a regulator of L1s.
“KAP1 is known to play a critical role in suppressing endogenous retroviruses, and has recently emerged as a regulator of L1s as well31,40.”
Quote in the paperSubstantial claim1 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationKAP1 is a pleiotropic regulator of diverse cellular processes including gene silencing, cell growth and differentiation, pluripotency, apoptosis, DNA repair, and maintenance of genomic integrity.
“KAP1 is a pleiotropic regulator of a diverse range of cellular processes ranging from gene silencing, cell growth and differentiation, pluripotency, apoptosis, DNA repair, and maintenance of genomic integrity39.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [39] Iyengar, S. & Farnham, P. J. KAP1 protein: an enigmatic master regulator of the genome. J. Biol. Chem. 286, 26267–26276 (2011). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSeveral neurological disorders, including Rhett Syndrome, Smith-Magenis syndrome and schizophrenia, are characterized by dysregulation of L1 activity.
“several neurological disorders, including Rhett Syndrome, Smith–Magenis syndrome and schizophrenia are characterized by dysregulation of L1 activity27,45,47.”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [27] Muotri, A. R. et al. L1 retrotransposition in neurons is modulated by MeCP2. Nature 468, 443–446 (2010). source
The paper’s main text (page unavailable) reports increased L1 retrotransposition in Rett syndrome neuronal progenitor cells and brain tissue compared with controls. It does not address Smith–Magenis syndrome or schizophrenia, so it supports only the Rett syndrome part of the sentence. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [45] Baillie, J. K. et al. Somatic retrotransposition alters the genetic landscape of the human brain. Nature 479, 534–537 (2011). source
The passage on disease implications (page unavailable in our copy) says MeCP2 deletion increases L1 copy number and may affect neuronal maturation in Rett syndrome. Another passage links RAI1 to Smith–Magenis syndrome and schizophrenia, but describes an Alu insertion in that gene—not dysregulated L1 activity in either disorder. The paper therefore does not support the claim for all three disorders. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [47] Jakovcevski, M. & Akbarian, S. Epigenetic mechanisms in neurological disease. Nat. Med. 18, 1194–1204 (2012). source
In “Mutations affecting DNA methylation and neurological disease” (page unavailable), the review links Rett syndrome to MeCP2 defects and reports de-repression of retrotransposons in MeCP2-deficient neuronal chromatin. It does not establish dysregulated L1 activity as a characteristic of Smith–Magenis syndrome or schizophrenia; its mention of schizophrenia concerns MECP2 variants, not L1 activity. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationRetrotransposition occurs more frequently in the brain, and in particular in the hippocampus and striatum, relative to other somatic tissues such as blood, heart and liver.
“Several other reports have indicated that retrotransposition occurs more frequently in the brain, and in particular in the hippocampus and striatum, relative to other somatic tissues, such as blood, heart and liver45,46.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [45] Baillie, J. K. et al. Somatic retrotransposition alters the genetic landscape of the human brain. Nature 479, 534–537 (2011). source
The paper’s Abstract reports somatic retrotransposon insertions in the hippocampus and caudate nucleus, a part of the striatum. It does not compare retrotransposition frequency in those regions with blood, heart, or liver, so the claimed higher frequency relative to those tissues is not supported by this copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [46] Coufal, N. G. et al. L1 retrotransposition in human neural progenitor cells. Nature 460, 1127–1131 (2009). source
The adult-tissue comparison (section labelled Abstract; page unavailable) found higher L1 ORF2 copy number in the hippocampus than in matched heart and liver, and a smaller increase across grouped brain regions. It included the caudate among sampled regions, but did not establish a separate striatal increase or compare brain tissue with blood. The authors also describe increased copy number as suggestive of retrotransposition, not proof that it occurs more frequently in the adult brain. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPost-translational modification of KAP1 plays a critical role in determining which cellular context the protein will function in.
“post-translational modification of KAP1 plays a critical role in determining which cellular context the protein will function in; for example sumoylated KAP1 promotes regulation of gene expression, while phosphorylated KAP1 promotes DNA repair41,42.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [41] Li, X. et al. Role for KAP1 serine 824 phosphorylation and sumoylation/desumoylation switch in regulating KAP1-mediated transcriptional repression. J. Biol. Chem. 282, 36177–36189 (2007). source
The Discussion (page not available in our copy) supports the general point that KAP1 phosphorylation and sumoylation affect its function: sumoylation is linked to transcriptional repression, while phosphorylation after DNA damage reduces sumoylation and relieves repression. It also reports phosphorylated KAP1 at DNA lesions with damage-response factors, but does not establish the citing sentence’s stronger example that phosphorylated KAP1 promotes DNA repair. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [42] White, D. et al. The ATM substrate KAP1 controls DNA repair in heterochromatin: regulation by HP1 proteins and serine 473/824 phosphorylation. Mol. Cancer Res. 10, 401–414 (2012). source
The Discussion (page unavailable) links KAP1 Ser 824 phosphorylation to effective DNA repair in heterochromatin, supporting the phosphorylation example. The paper also discusses KAP1-mediated gene silencing, but its text does not establish the sentence’s specific claim that sumoylated KAP1 regulates gene expression or that modifications determine mutually distinct functions; it reports that gene-silencing activity does not diminish in irradiated cells. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationSIRT6 promotes DNA double strand break repair, regulates telomere stability, suppresses inflammation and opposes tumorigenesis.
“SIRT6 promotes DNA double strand break repair19,20, regulates telomere stability21, suppresses inflammation22 and opposes tumorigenesis23,24.”
Quote in the paperNot a substantial claim4 of 4 sources checked- cites [19] Mao, Z. et al. SIRT6 promotes DNA repair under stress by activating PARP1. Science 332, 1443–1446 (2011). source
- cites [20] Kaidi, A., Weinert, B. T., Choudhary, C. & Jackson, S. P. Human SIRT6 promotes DNA end resection through CtIP deacetylation. Science 329, 1348–1353 (2010). source
- cites [21] Michishita, E. et al. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 452, 492–496 (2008). source
- cites [22] Kawahara, T. L. et al. SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell 136, 62–74 (2009). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDe novo insertions of retrotransposons preferentially affect actively transcribed genes in the brain, including dopamine receptors, amino acid transporters and genes regulating synaptic transmission.
“de novo insertions of retrotransposons appear to preferentially affect actively transcribed genes in the brain, including dopamine receptors, amino acid transporters and genes regulating synaptic transmission45.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [45] Baillie, J. K. et al. Somatic retrotransposition alters the genetic landscape of the human brain. Nature 479, 534–537 (2011). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSIRT6 has been reported to mono-ADP ribosylate PARP1.
“SIRT6 has been reported to mono-ADP ribosylate PARP119”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [19] Mao, Z. et al. SIRT6 promotes DNA repair under stress by activating PARP1. Science 332, 1443–1446 (2011). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationL1 retrotransposon activity has been linked to DNA damage, mutagenesis, and deregulation of host gene transcription.
“Long interspersed element 1 (L1) retrotransposon activity, in particular, has been linked to DNA damage5, mutagenesis6,7, and deregulation of host gene transcription8.”
Quote in the paperNot a substantial claim3 of 4 sources checked- cites [5] Gasior, S. L., Wakeman, T. P., Xu, B. & Deininger, P. L. The human LINE-1 retrotransposon creates DNA double-strand breaks. J. Mol. Biol. 357, 1383–1393 (2006). source
- cites [6] Gilbert, N., Lutz-Prigge, S. & Moran, J. V. Genomic deletions created upon LINE-1 retrotransposition. Cell 110, 315–325 (2002). source
- cites [7] Iskow, R. C. et al. Natural mutagenesis of human genomes by endogenous retrotransposons. Cell 141, 1253–1261 (2010). source
- cites [8] Han, J. S., Szak, S. T. & Boeke, J. D. Transcriptional disruption by the L1 retrotransposon and implications for mammalian transcriptomes. Nature 429, 268–274 (2004). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSenescent cells have been implicated in the etiology of aging.
“Senescent cells, which have been implicated in the etiology of aging35”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [35] van Deursen, J. M. The role of senescent cells in ageing. Nature 509, 439–446 (2014). source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe episomal L1-EGFP reporter plasmid and the L1 5′UTR-Luciferase reporter plasmid used in this study were both described previously.
“The episomal L1-EGFP reporter plasmid and the L1 5′UTR-Luciferase reporter plasmid used in this study were both described previously25,50.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [25] Ostertag, E. M., Prak, E. T., DeBerardinis, R. J., Moran, J. V. & Kazazian, H. H. Jr. Determination of L1 retrotransposition kinetics in cultured cells. Nucleic Acids Res. 28, 1418–1423 (2000). source
- cites [50] Athanikar, J. N., Badge, R. M. & Moran, J. V. A YY1-binding site is required for accurate human LINE-1 transcription initiation. Nucleic Acids Res. 32, 3846–3855 (2004). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationL1 activity has been implicated in a variety of age-related disorders, including cancer and neurodegeneration.
“L1 activity has been implicated in a variety of age-related disorders12, including cancer7,13 and neurodegeneration14,15.”
Quote in the paperNot a substantial claim5 of 5 sources checked- cites [12] Hancks, D. C. & Kazazian, H. H. Jr. Active human retrotransposons: variation and disease. Curr. Opin. Genet. Dev. 22, 191–203 (2012). source
The INSERTIONS AND DISEASE section reports multiple disease-causing retrotransposon insertions, and TIMING OF RETROTRANSPOSITION says somatic L1 activity may play a role in tumorigenesis. But the copy does not characterize these as age-related disorders or link L1 activity to neurodegeneration; its discussion of brain activity mentions Rett syndrome instead. In the citing sentence, the separate cancer and neurodegeneration citations do not establish those points for this source. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [7] Iskow, R. C. et al. Natural mutagenesis of human genomes by endogenous retrotransposons. Cell 141, 1253–1261 (2010). source
- cites [13] Lee, E. et al. Landscape of somatic retrotransposition in human cancers. Science 337, 967–971 (2012). source
- cites [14] Reilly, M. T., Faulkner, G. J., Dubnau, J., Ponomarev, I. & Gage, F. H. The role of transposable elements in health and diseases of the central nervous system. J. Neurosci. 33, 17577–17586 (2013). source
- cites [15] Tan, H. et al. Retrotransposon activation contributes to fragile X premutation rCGG-mediated neurodegeneration. Hum. Mol. Genet. 21, 57–65 (2012). source
The Discussion reports that retrotransposon activation contributes to neurodegeneration in a fragile X fly model, supporting the neurodegeneration portion at the level of retrotransposons generally. It identifies gypsy, not L1, as the retrotransposon whose reduction suppresses neuronal toxicity; its discussion of cancer likewise does not implicate L1 specifically. The paper therefore does not support the broader claim about L1 activity across age-related disorders. (LLM, conf=0.87)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationMechanisms that silence retrotransposons in somatic cells are not completely efficient and may deteriorate with age.
“evidence has begun to accumulate indicating that the mechanisms which silence retrotransposons in somatic cells are not completely efficient9 and may deteriorate with age10,11.”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [9] Belancio, V. P., Roy-Engel, A. M., Pochampally, R. R. & Deininger, P. Somatic expression of LINE-1 elements in human tissues. Nucleic Acids Res. 38, 3909–3922 (2010). source
- cites [10] De Cecco, M. et al. Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging Cell 12, 247–256 (2013). source
- cites [11] St Laurent, G. 3rd, Hammell, N. & McCaffrey, T. A. A LINE-1 component to human aging: do LINE elements exact a longevity cost for evolutionary advantage? Mech. Ageing Dev. 131, 299–305 (2010). source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationSIRT6 has multiple biochemical activities, including protein deacetylation and mono-ADP ribosylation.
“SIRT6 has multiple biochemical activities, including protein deacetylation22 and mono-ADP ribosylation19,29.”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [22] Kawahara, T. L. et al. SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell 136, 62–74 (2009). source
The citation to this paper is attached to mono-ADP ribosylation, not to protein deacetylation. The Introduction and Discussion describe SIRT6 as an H3K9 deacetylase, but searches for mono-ADP ribosylation, ADP-ribosylation, and ADP-ribosyltransferase found no passage addressing that activity. Page numbers were not available in our copy. (LLM, conf=0.72)
Experimental — accuracy not yet measured - cites [19] Mao, Z. et al. SIRT6 promotes DNA repair under stress by activating PARP1. Science 332, 1443–1446 (2011). source
- cites [29] Liszt, G., Ford, E., Kurtev, M. & Guarente, L. Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase. J. Biol. Chem. 280, 21313–21320 (2005). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPARP1 has been implicated in the silencing of retrotransposons in Drosophila.
“a protein which has been implicated in the silencing of retrotransposons in Drosophila30”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [30] Tulin, A., Stewart, D. & Spradling, A. C. The Drosophila heterochromatic gene encoding poly(ADP-ribose) polymerase (PARP) is required to modulate chromatin structure during development. Genes Dev. 16, 2108–2119 (2002). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe luciferase assay using the L1-5′UTR reporter has been previously described.
“The luciferase assay using the L1-5′UTR reporter has been previously described50.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [50] Athanikar, J. N., Badge, R. M. & Moran, J. V. A YY1-binding site is required for accurate human LINE-1 transcription initiation. Nucleic Acids Res. 32, 3846–3855 (2004). source
Classified as probably not a substantial claim.
PremisecitationIn vitro mono-ADP ribosylation experiments were conducted essentially as previously described.
“In vitro mono-ADP ribosylation experiments were conducted essentially as previously described19.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [19] Mao, Z. et al. SIRT6 promotes DNA repair under stress by activating PARP1. Science 332, 1443–1446 (2011). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThese bisulfite primers have been previously described.
“These primers have been previously described51.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [51] Kaneda, M. et al. Genetic evidence for Dnmt3a-dependent imprinting during oocyte growth obtained by conditional knockout with Zp3-Cre and complete exclusion of Dnmt3b by chimera formation. Genes Cells 15 169–179 (2010). source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationThe vast majority of L1s in the human genome are 5′ truncated; average L1 length is approximately 900 bp and 90-95% of all L1s are 5′ truncated.
“As the vast majority of L1s in the human genome are 5′ truncated (average L1 length is approximately 900bp, 90-95% of all L1s are 5′trunctated), this analysis was unsurprisingly skewed towards the 3′ end of L1s.”
- Also stated in: § ChIP-seq analysis · plain
“Multiple reports have described the ratio of human L1s that are truncated, we used these reports as the basis for adjusting raw read depth to normalized read depth53,54.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [53] Szak, S. T. et al. Molecular archeology of L1 insertions in the human genome. Genome Biol 3, research0052 (2002). source
The Results section, “Characteristics of 5′ truncated L1 elements” (page not provided), says most human L1s are 5′ truncated and only 5% of the study’s 3′-intact L1s were full-length. That supports roughly 95% truncation for that subset, not explicitly for all L1s. The copy does not support an average length of approximately 900 bp; “Gene neighborhood of L1 insertions” instead reports a 1,614-nucleotide mean for the TSD-containing set. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [54] O'Geen, H. et al. Genome-wide analysis of KAP1 binding suggests autoregulation of KRAB-ZNFs. PLoS Genet. 3, e89 (2007). source
The Results section, “Identification of KAP1 Targets on a Genome-Wide Scale” (page unavailable), discusses KAP1 binding sites and an average binding-site span of 820 bp, not L1 length. Searches for L1/LINE-1, 5′ truncation, 900 bp, and 90–95% found no passage in our copy addressing the attributed L1 statistics. (LLM, conf=0.75)
Experimental — accuracy not yet measured
- Also stated in: § ChIP-seq analysis · plain
May combine two claims.
Findingown dataMeCP2 and KAP1 are depleted from the L1 5′UTR in SIRT6 KO cells.
“the heterochromatin regulating proteins MeCP2 (methyl CpG binding protein 2) and KAP1 (KRAB-associated protein 1) were also depleted from the L1 5′UTR in SIRT6 KO cells (Fig. 2c; Supplementary Fig. 7b, c).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataOverexpression of WT SIRT6 and SIRT6 R65A restores KAP1-HP1α interactions to wild-type levels, whereas SIRT6 G60A or SIRT6 S56Y fail to restore them.
“Overexpression of WT SIRT6 and SIRT6 R65A was sufficient to restore KAP1-HP1α interactions to wild-type levels; in contrast, overexpression of SIRT6 G60A or SIRT6 S56Y failed to restore KAP1-HP1α interactions (Fig. 3e).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSIRT6 transfers radiolabelled NAD+ to KAP1, but not to any other substrate tested.
“SIRT6 transferred radiolabelled NAD+ to KAP1, but not to any other substrate tested (Fig. 3b).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThe final set of unique sequences after filtering was 2,548,326.
“creating a final set of 2,548,326 unique sequences.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
FindingreasoningReference alignment of SIRT6 ChIP-seq reads to a full-length L1 sequence was skewed towards the 3′ end of L1s.
“this analysis was unsurprisingly skewed towards the 3′ end of L1s.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThe vast majority of sequences in the SIRT6 ChIP-seq dataset appeared exactly once.
“The vast majority of sequences appeared exactly once.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataSIRT6 and KAP1 cooperate to suppress retroelements but have divergent functions in regulation of gene expression.
“suggesting that SIRT6 and Kap1 cooperate to suppress retroelements but have divergent functions in regulation of gene expression (Supplementary Fig. 14a-c).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataSIRT6 is normally localized to L1 loci, repressing their transcription by mono-ADP-ribosylating KAP1 and facilitating its interaction with HP1α; in response to stress, SIRT6 vacates these sites to facilitate DNA repair, creating a window for increased L1 activity.
“This suggests a paradigm wherein SIRT6 is normally localized to L1 loci, repressing their transcription by mono-ADP-ribosylating Kap1 and facilitating its interaction with HP1α; in response to stress, however, SIRT6 vacates these sites in order to facilitate DNA repair, creating a window for increased L1 activity”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationSIRT6 knockout mice develop a severe premature aging syndrome characterized by genomic instability, curvature of the spine, decreased bone mineral density, hypoglycemia and a severely shortened lifespan.
“SIRT6 knockout mice develop a severe premature aging syndrome, characterized by genomic instability, curvature of the spine, decreased bone mineral density, hypoglycemia and a severely shortened lifespan16.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Mostoslavsky, R. et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124, 315–329 (2006). source
May combine two claims.
Interpretationown dataL1 activity in the brain is particularly sensitive to upregulation during aging and in the absence of SIRT6.
“our observation that L1 activity in the brain is particularly sensitive to upregulation during aging and in the absence of SIRT6.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationMice overexpressing SIRT6 exhibit extended mean and median lifespans, concomitant with improved metabolic function and cancer resistance.
“mice overexpressing SIRT6 exhibit extended mean and median lifespans, concomitant with improved metabolic function17 and cancer resistance18.”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
InterpretationreasoningDerepression of L1 in response to SIRT6 mobilization to DNA damage sites represents a threat to genome stability and may be important in the manifestation of aging.
“derepression of L1 in response to SIRT6 mobilization to DNA damage sites represents a threat to genome stability and may be important in the manifestation of aging.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationKAP1 has been reported to induce silencing of endogenous retroelements in part by coordinating the assembly of a HP1α-SETDB1 dependent co-repressor complex.
“KAP1 has been reported to induce silencing of endogenous retroelements31 in part by coordinating the assembly of a HP1α-SETDB1 dependent co-repressor complex32.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [31] Rowe, H. M. et al. KAP1 controls endogenous retroviruses in embryonic stem cells. Nature 463, 237–240 (2010). source
- cites [32] Sripathy, S. P., Stevens, J. & Schultz, D. C. The KAP1 corepressor functions to coordinate the assembly of de novo HP1-demarcated microenvironments of heterochromatin required for KRAB zinc finger protein-mediated transcriptional repression. Mol. Cell. Biol. 26, 8623–8638 (2006). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSIRT6 is a key regulator of mammalian lifespan.
“Several mouse models have suggested that SIRT6 is a key regulator of mammalian lifespan.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [16] Mostoslavsky, R. et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124, 315–329 (2006). source
- cites [17] Kanfi, Y. et al. SIRT6 protects against pathological damage caused by diet-induced obesity. Aging Cell 9, 162–173 (2010). source
- cites [18] Kanfi, Y. et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature 483, 218–221 (2012). source
Classified as probably not a substantial claim.
Study design and conductreasoningMEFs from SIRT6 KO and WT embryos were subject to an equal number of passages during cell line expansion prior to analysis for new L1 insertions.
“These cells were subject to an equal number of passages during cell line expansion, prior to analysis for new L1 insertions.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductnone givenRelative protein binding in ChIP was calculated after normalization to input and IgG controls.
“Relative protein binding was calculated after normalization to input and IgG controls.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningUnique reads were excluded from subsequent analysis of read frequency to exclude reads generated by sequencing error.
“We excluded these reads from subsequent analysis of read frequency, to exclude any unique reads generated by sequencing error”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningCells expressing a stably integrated L1 5′UTR luciferase reporter were passaged for four weeks to ensure that luciferase signal was generated by stably integrated L1-5′UTR reporter.
“The cells were passaged for four weeks to ensure that luciferase signal was generated by stably integrated L1-5′UTR reporter.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataqRT-PCR values were standardized to housekeeping gene expression (ACTIN and HPRT).
“Values were standardized to housekeeping gene expression (ACTIN and HPRT); data was analyzed using the comparative CT method.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataLuciferase experiments were repeated three times, in triplicate each time.
“Experiments were repeated three times, in triplicate each time.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataPrimer efficiency for qRT-PCR was verified by linear regression to a standard curve using serial dilutions.
“Primer efficiency was verified by linear regression to a standard curve using 2, 1, 1/2, 1/4, 1/8, 1/16, 1/32, 1/64 and 1/128 dilutions.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningExcluding reads that appeared exactly once has the effect of making the measure of frequency more conservative.
“This also has the effect of making our measure of frequency more conservative.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataqRT-PCR reactions were carried out in quadruplicate.
“Reactions were carried out in quadruplicate at 95°C for 10 min, followed by 40 cycles of 45 s at 95°C and 45s at 60°C and 45 s at 72°C.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataAn IgG control was used for each ChIP precipitation experiment.
“an IgG control was used for each precipitation experiment.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataAll micrococcal nuclease experiments were performed in triplicate.
“All experiments were performed in triplicate, a representative experiment is shown.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningUsing cell cycle synchronized MEFs derived from littermate embryos that had been subject to the same number of passages reduced potential artifacts generated by DNA replication and differing amounts of cell divisions.
“By using cell cycle synchronized cells, derived from littermate embryos, that had been subject to the same number of passages, we reduced potential artifacts generated by DNA replication and differing amounts of cell divisions.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataBisulfite primers did not amplify untreated genomic DNA.
“As a negative control, we confirmed that these primers did not amplify untreated genomic DNA.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenRelative genomic ORF2 content was normalized to 5S genomic content.
“Relative genomic ORF2 content normalized to 5S genomic content.”
Quote in the paperSubstantial claim- Rests on an assumption: The 5S ribosomal RNA sequence is non-mobile and its genomic content is a valid normalization control for ORF2 genomic content.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenLuciferase activity was normalized to the number of cells harvested.
“Luciferase activity was normalized to the number of cells harvested.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataThe qPCR experiment used 60 wells per sample and was performed three times, with different mice contributing cells for each repeat.
“60 wells were used for each sample, the experiment was performed three times, with different mice contributing cells for each repeat.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
L1 ORF2 encodes an endonuclease that induces DNA damage when expressed.
“the L1 ORF2 encodes an endonuclease which, when expressed induces DNA damage”
The paper relies on this without support.
Massive L1 transcriptional activity can induce mis-regulation of host gene expression and clog the host transcriptional machinery.
“massive L1 transcriptional activity itself, can induce mis-regulation of gene expression and ‘clog’ the transcriptional machinery of the host”
The paper relies on this without support.
L1 retrotransposons are the most active members of the mammalian retrotransposon family.
“L1 retrotransposons, the most active members of the mammalian retrotransposon family”
The paper relies on this without support.
L1 transcription is driven by an internal promoter within the L1 5′UTR.
“L1 transcription is driven by an internal promoter within the L1 5′UTR.”
The paper relies on this without support.
KAP1 enforces silencing by facilitating the recruitment of additional silencing factors at the target locus.
“KAP1 appears to enforce silencing by facilitating the recruitment of additional silencing factors at the target locus.”
The paper relies on this without support.
All antibodies used have previously been verified in ChIP.
“All antibodies used have previously been verified in ChIP.”
The paper relies on this without support.
The ratio of truncated human L1s from prior reports is applicable to the SIRT6 ChIP-seq data and cell types analyzed.
“Multiple reports have described the ratio of human L1s that are truncated, we used these reports as the basis for adjusting raw read depth to normalized read depth53,54.”
The paper relies on this without support.
The 5S ribosomal RNA sequence is non-mobile and its genomic content is a valid normalization control for ORF2 genomic content.
“Control primers targeted non-mobile 5S ribosomal RNA sequence (Forward: 5′-acggccataccaccctgaa-3′ and Reverse: 5′- ggtctcccatccaagtactaacca-3′).”
“Relative genomic ORF2 content normalized to 5S genomic content.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
SIRT6 promotes L1 silencing by binding to the L1 5′ UTR and mono-ADP ribosylating KAP1, which then recruits HP1a and MeCP2.
“One possible senescence-independent mechanism involves SIRT6, which promotes L1 silencing by binding to the L1 5’ UTR and mono-ADP ribosylating KAP1, which then recruits additional heterochromatin factors HP1a and MeCP231.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [31]
The Results report SIRT6 enrichment at the L1 5′ UTR and show that it mono-ADP ribosylates KAP1; the Discussion says this modification is required to recruit HP1α to L1 loci (pages unavailable). The Results also show that MeCP2 is depleted from L1 loci without SIRT6, but do not establish that ribosylated KAP1 recruits MeCP2. The claim overstates that final mechanistic link. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLoss of heterochromatin factors reduces heterochromatin at retrotransposons and allows their transcriptional derepression.
“Loss of these factors reduces heterochromatin at retrotransposons and allows their transcriptional derepression26, 29, 31, 33–35.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [31]
SIRT6 relocalizes to DNA damage sites.
“The upstream stimuli that initiate compromise of surveillance systems are beginning to come into view (for example, SIRT6 relocalization to sites of DNA damage31, or L1 chromatin opening due to TDP-43 relocalization into the cytoplasm130), but our understanding of these mechanisms is still very primitive.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [31]
SIRT6 acts as an epigenetic regulator.
“One such epigenetic regulator is SIRT631.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [31]
SIRT6 represses L1 activity by binding to the 5' UTR of L1 elements and promoting heterochromatinization through facilitating interaction of KAP1 with HP1α.
“SIRT6 represses L1 activity by binding to the 5’ UTR of L1 elements and promotes heterochromatinization by facilitating the interaction of KAP1 with the heterochromatin factor, HP1α, thus rendering L1 elements transcriptionally inactive (Van Meter et al., 2014).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Van Meter et al., 2014
During senescence and in brains of aged mice, SIRT6 is depleted from L1 loci, allowing L1 expression and retrotransposition.
“However, during senescence and in brains of aged mice, SIRT6 is depleted from L1 loci, allowing L1 expression and retrotransposition to occur (Van Meter et al., 2014).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Van Meter et al., 2014
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Self-check results appear here once an independent check has confirmed them.
Cited works that were retracted
Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.
Cites a retracted work: 10.1126/science.1192049
InfoThe cited work was retracted on 2019-04-11 (notice 10.1126/science.aax4558), not before this paper was published (2014-09-23).
Cited work 10.1126/science.1192049 · retracted 2019-04-11 · notice 10.1126/science.aax4558 · this paper published 2014-09-23
“Kaidi, A., Weinert, B. T., Choudhary, C. & Jackson, S. P. Human SIRT6 promotes DNA end resection through CtIP deacetylation. Science 329, 1348–1353 (2010).”
Cites
1 retracted
RETRACTED: Human SIRT6 Promotes DNA End Resection Through CtIP Deacetylation
Kaidi, A., Weinert, B. T., Choudhary, C., & Jackson, S. P. (2010) · Science · doi:10.1126/science.1192049 · Cited by 366 · see citing works
RetractedFast and accurate short read alignment with Burrows-Wheeler transform
Li, H., & Durbin, R. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp324 · Cited by 58,607 · see citing works
Initial sequencing and analysis of the human genome
International Human Genome Sequencing Consortium, Whitehead Institute for Biomedical Research, C. F. G. R., Lander, E. S., Linton, L. M., Birren, B., Nusbaum, C., Zody, M. C., Baldwin, J., Devon, K., Dewar, K., et al. (2001) · Nature · doi:10.1038/35057062 · Cited by 24,216 · cited 1× · see citing works
“Retrotransposons comprise a significant fraction of mammalian genomes 1,2 , and are potent mediators of genomic instability 3,4 .”
Initial sequencing and comparative analysis of the mouse genome
Mouse Genome Sequencing Consortium (2002) · Nature · doi:10.1038/nature01262 · Cited by 7,187 · see citing works
The role of senescent cells in ageing
van Deursen, J. M. (2014) · Nature · doi:10.1038/nature13193 · Cited by 2,623 · cited 1× · see citing works
“Senescent cells, which have been implicated in the etiology of aging 35 , exhibited a 3.1 fold increase in L1 mRNA levels (Fig.”
InfluentialHoeijmakers, J. H. J. (2009) · New England Journal of Medicine · doi:10.1056/nejmra0804615 · Cited by 2,239 · cited 1× · see citing works
“DNA damage is more abundant in old cells and tissues 37,38 .”
The impact of retrotransposons on human genome evolution
Cordaux, R., & Batzer, M. (2009) · Nature reviews genetics · doi:10.1038/nrg2640 · Cited by 1,691 · cited 1× · see citing works
“Retrotransposons comprise a significant fraction of mammalian genomes 1,2 , and are potent mediators of genomic instability 3,4 .”
Genomic Instability and Aging-like Phenotype in the Absence of Mammalian SIRT6
Mostoslavsky, R., Chua, K. F., Lombard, D. B., Pang, W. W., Fischer, M. R., Gellon, L., Liu, P., Mostoslavsky, G., Franco, S., Murphy, M. M., et al. (2006) · Cell · doi:10.1016/j.cell.2005.11.044 · Cited by 1,637 · see citing works
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“Additional factors that may contribute to reduced SIRT6-mediated L1 silencing are declining levels of nuclear NAD+ 56 and lower levels of SIRT6 in senescent cells 57 .”
Michishita, E., Park, J. Y., Burneskis, J. M., Barrett, J. C., & Horikawa, I. (2005) · Molecular Biology of the Cell · doi:10.1091/mbc.e05-01-0033 · Cited by 1,364 · cited 1× · see citing works
“Because SIRT6 is a chromatin-associated protein 26 , we hypothesized that SIRT6 may attenuate L1 activity by preventing transcription of L1 loci.”
SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin
Michishita, E., McCord, R. A., Berber, E., Kioi, M., Padilla-Nash, H., Damian, M., Cheung, P., Kusumoto, R., Kawahara, T. L. A., Barrett, J. C., et al. (2008) · Nature · doi:10.1038/nature06736 · Cited by 1,111 · see citing works
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Hot L1s account for the bulk of retrotransposition in the human population
Brouha, B., Schustak, J., Badge, R. M., Lutz-Prigge, S., Farley, A. H., Moran, J. V., & Kazazian, H. H. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0831042100 · Cited by 1,073 · cited 1× · see citing works
“Retrotransposons comprise a significant fraction of mammalian genomes 1,2 , and are potent mediators of genomic instability 3,4 .”
The sirtuin SIRT6 regulates lifespan in male mice
Kanfi, Y., Naiman, S., Amir, G., Peshti, V., Zinman, G., Nahum, L., Bar-Joseph, Z., & Cohen, H. Y. (2012) · Nature · doi:10.1038/nature10815 · Cited by 1,059 · see citing works
KAP1 controls endogenous retroviruses in embryonic stem cells
Rowe, H. M., Jakobsson, J., Mesnard, D., Rougemont, J., Reynard, S., Aktas, T., Maillard, P. V., Layard-Liesching, H., Verp, S., Marquis, J., et al. (2010) · Nature · doi:10.1038/nature08674 · Cited by 874 · cited 2× · see citing works
“KAP1 has been reported to induce silencing of endogenous retroelements 31 in part by coordinating the assembly of a HP1 α - SETDB1 dependent co-repressor complex 32 .”
SIRT6 Promotes DNA Repair Under Stress by Activating PARP1
Mao, Z., Hine, C., Tian, X., Van Meter, M., Au, M., Vaidya, A., Seluanov, A., & Gorbunova, V. (2011) · Science · doi:10.1126/science.1202723 · Cited by 867 · cited 4× · see citing works
“SIRT6 is known to rapidly relocalize to DNA damage sites in response to oxidative stress 19,36 .”
InfluentialSelf-citationSIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging
Oberdoerffer, P., Michan, S., McVay, M., Mostoslavsky, R., Vann, J., Park, S.-K., Hartlerode, A., Stegmuller, J., Hafner, A., Loerch, P., et al. (2008) · Cell · doi:10.1016/j.cell.2008.10.025 · Cited by 852 · see citing works
L1 retrotransposition in human neural progenitor cells
Coufal, N. G., Garcia-Perez, J. L., Peng, G. E., Yeo, G. W., Mu, Y., Lovci, M. T., Morell, M., O’Shea, K. S., Moran, J. V., & Gage, F. H. (2009) · Nature · doi:10.1038/nature08248 · Cited by 814 · cited 1× · see citing works
“Several other reports have indicated that retrotransposition occurs more frequently in the brain, and in particular in the hippocampus and striatum, relative to other somatic tissues, such as blood, heart and liver 45,46 .”
Landscape of Somatic Retrotransposition in Human Cancers
Lee, E., Iskow, R., Yang, L., Gokcumen, O., Haseley, P., Luquette, L. J., Lohr, J. G., Harris, C. C., Ding, L., Wilson, R. K., et al. (2012) · Science · doi:10.1126/science.1222077 · Cited by 762 · cited 1× · see citing works
“Consistent with this observation, L1 activity has been implicated in a variety of age-related disorders 12 , including cancer 7,13 and neurodegeneration 14,15 .”
Somatic retrotransposition alters the genetic landscape of the human brain
Baillie, J. K., Barnett, M. W., Upton, K. R., Gerhardt, D. J., Richmond, T. A., De Sapio, F., Brennan, P. M., Rizzu, P., Smith, S., Fell, M., et al. (2011) · Nature · doi:10.1038/nature10531 · Cited by 684 · cited 3× · see citing works
“…have led to the hypothesis that deregulation of L1s may contribute to disease pathogenesis in the brain; consistent with this notion, several neurological disorders, including Rhett Syndrome, Smith–Magenis syndrome and schizophrenia are characterized by dysregulation of L1 activity 27,45,47 .”
The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism
Sebastián, C., Zwaans, B. M. M., Silberman, D. M., Gymrek, M., Goren, A., Zhong, L., Ram, O., Truelove, J., Guimaraes, A. R., Toiber, D., et al. (2012) · Cell · doi:10.1016/j.cell.2012.10.047 · Cited by 660 · see citing works
L1 retrotransposition in neurons is modulated by MeCP2
Muotri, A. R., Marchetto, M. C. N., Coufal, N. G., Oefner, R., Yeo, G., Nakashima, K., & Gage, F. H. (2010) · Nature · doi:10.1038/nature09544 · Cited by 626 · cited 3× · see citing works
“Finally, using a sensitive qPCR method for detecting de novo retroelement insertions 27 , we found that SIRT6 KO MEFs had elevated genomic L1 DNA content, indicating that retrotransposition events occur more frequently in SIRT6 KO cells, relative to WT (Fig.”
Active human retrotransposons: variation and disease
Hancks, D. C., & Kazazian, H. H. (2012) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2012.02.006 · Cited by 592 · cited 1× · see citing works
“Consistent with this observation, L1 activity has been implicated in a variety of age-related disorders 12 , including cancer 7,13 and neurodegeneration 14,15 .”
Natural mutagenesis of human genomes by endogenous retrotransposons
Iskow, R. C., McCabe, M. T., Mills, R. E., Torene, S., Pittard, W. S., Neuwald, A. F., Van Meir, E. G., Vertino, P. M., & Devine, S. E. (2010) · Cell · doi:10.1016/j.cell.2010.05.020 · Cited by 551 · cited 2× · see citing works
“Long interspersed element 1 (L1) retrotransposon activity, in particular, has been linked to DNA damage 5 , mutagenesis 6,7 , and deregulation of host gene transcription 8 .”
Mouse Sir2 Homolog SIRT6 Is a Nuclear ADP-ribosyltransferase
Liszt, G., Ford, E., Kurtev, M., & Guarente, L. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m413296200 · Cited by 548 · cited 1× · see citing works
“SIRT6 has multiple biochemical activities, including protein deacetylation 22 and mono-ADP ribosylation 19,29 .”
The Human LINE-1 Retrotransposon Creates DNA Double-strand Breaks
Gasior, S. L., Wakeman, T. P., Xu, B., & Deininger, P. L. (2006) · Journal of Molecular Biology · doi:10.1016/j.jmb.2006.01.089 · Cited by 519 · cited 1× · see citing works
“Long interspersed element 1 (L1) retrotransposon activity, in particular, has been linked to DNA damage 5 , mutagenesis 6,7 , and deregulation of host gene transcription 8 .”
Transcriptional disruption by the L1 retrotransposon and implications for mammalian transcriptomes
Han, J. S., Szak, S. T., & Boeke, J. D. (2004) · Nature · doi:10.1038/nature02536 · Cited by 484 · cited 1× · see citing works
“Long interspersed element 1 (L1) retrotransposon activity, in particular, has been linked to DNA damage 5 , mutagenesis 6,7 , and deregulation of host gene transcription 8 .”
Genomic Deletions Created upon LINE-1 Retrotransposition
Gilbert, N., Lutz-Prigge, S., & Moran, J. V. (2002) · Cell · doi:10.1016/s0092-8674(02)00828-0 · Cited by 474 · cited 1× · see citing works
“Long interspersed element 1 (L1) retrotransposon activity, in particular, has been linked to DNA damage 5 , mutagenesis 6,7 , and deregulation of host gene transcription 8 .”
De Cecco, M., Criscione, S. W., Peckham, E. J., Hillenmeyer, S., Hamm, E. A., Manivannan, J., Peterson, A. L., Kreiling, J. A., Neretti, N., & Sedivy, J. M. (2013) · Aging Cell · doi:10.1111/acel.12047 · Cited by 459 · cited 2× · see citing works
“Cumulatively this study builds on the mounting body of evidence which suggests that L1s become more transcriptionally active during aging and senescence 10,49 , and provides a molecular mechanism to explain this phenomenon.”
Epigenetic mechanisms in neurological disease
Jakovcevski, M., & Akbarian, S. (2012) · Nature Medicine · doi:10.1038/nm.2828 · Cited by 450 · see citing works
KAP1 Protein: An Enigmatic Master Regulator of the Genome
Iyengar, S., & Farnham, P. J. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.r111.252569 · Cited by 367 · cited 1× · see citing works
“KAP1 is a pleiotropic regulator of a diverse range of cellular processes ranging from gene silencing, cell growth and differentiation, pluripotency, apoptosis, DNA repair, and maintenance of genomic integrity 39 .”
Transposable elements become active and mobile in the genomes of aging mammalian somatic tissues
De Cecco, M., Criscione, S. W., Peterson, A. L., Neretti, N., Sedivy, J. M., & Kreiling, J. A. (2013) · Aging · doi:10.18632/aging.100621 · Cited by 365 · cited 1× · see citing works
“Cumulatively this study builds on the mounting body of evidence which suggests that L1s become more transcriptionally active during aging and senescence 10,49 , and provides a molecular mechanism to explain this phenomenon.”
Ram, O., Goren, A., Amit, I., Shoresh, N., Yosef, N., Ernst, J., Kellis, M., Gymrek, M., Issner, R., Coyne, M., et al. (2011) · Cell · doi:10.1016/j.cell.2011.09.057 · Cited by 331 · see citing works
Sripathy, S. P., Stevens, J., & Schultz, D. C. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.00487-06 · Cited by 323 · cited 1× · see citing works
“KAP1 has been reported to induce silencing of endogenous retroelements 31 in part by coordinating the assembly of a HP1 α - SETDB1 dependent co-repressor complex 32 .”
SIRT6 protects against pathological damage caused by diet‐induced obesity
Kanfi, Y., Peshti, V., Gil, R., Naiman, S., Nahum, L., Levin, E., Kronfeld‐Schor, N., & Cohen, H. Y. (2010) · Aging Cell · doi:10.1111/j.1474-9726.2009.00544.x · Cited by 311 · see citing works
Determination of L1 retrotransposition kinetics in cultured cells
Ostertag, E. M. (2000) · Nucleic Acids Research · doi:10.1093/nar/28.6.1418 · Cited by 291 · cited 2× · see citing works
“To examine whether SIRT6 plays a role in suppressing L1 retrotransposition, we used a L1-EGFP reporter cassette 25 (Supplementary Fig.”
Somatic expression of LINE-1 elements in human tissues
Belancio, V. P., Roy-Engel, A. M., Pochampally, R. R., & Deininger, P. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq132 · Cited by 238 · cited 2× · see citing works
“Indeed, overexpression of exogenous full length L1 has been shown to induce a senescence-like phenotype in human fibroblasts and adult stem cells 9 .”
Molecular archeology of L1 insertions in the human genome
Szak, S. T., Pickeral, O. K., Makalowski, W., Boguski, M. S., Landsman, D., & Boeke, J. D. (2002) · Genome Biology · doi:10.1186/gb-2002-3-10-research0052 · Cited by 230 · cited 1× · see citing works
“Multiple reports have described the ratio of human L1s that are truncated, we used these reports as the basis for adjusting raw read depth to normalized read depth 53,54 .”
Evolutionally dynamic L1 regulation in embryonic stem cells
Castro-Diaz, N., Ecco, G., Coluccio, A., Kapopoulou, A., Yazdanpanah, B., Friedli, M., Duc, J., Jang, S. M., Turelli, P., & Trono, D. (2014) · Genes & Development · doi:10.1101/gad.241661.114 · Cited by 225 · cited 1× · see citing works
“Of particular interest to this study, KAP1 is known to play a critical role in suppressing endogenous retroviruses, and has recently emerged as a regulator of L1s as well 31,40 .”
Tulin, A., Stewart, D., & Spradling, A. C. (2002) · Genes & Development · doi:10.1101/gad.1003902 · Cited by 204 · cited 1× · see citing works
“SIRT6 has been reported to mono-ADP ribosylate PARP1 19 , a protein which has been implicated in the silencing of retrotransposons in Drosophila 30 ; however, in our system, PARP1 was dispensable for SIRT6 mediated silencing of L1s (Supplementary Fig.”
A YY1-binding site is required for accurate human LINE-1 transcription initiation
Athanikar, J. N. (2004) · Nucleic Acids Research · doi:10.1093/nar/gkh698 · Cited by 200 · cited 1× · see citing works
“The episomal L1-EGFP reporter plasmid and the L1 5 ′ UTR-Luciferase reporter plasmid used in this study were both described previously 25,50 .”
Genome-Wide Analysis of KAP1 Binding Suggests Autoregulation of KRAB-ZNFs
O'Geen, H., Squazzo, S. L., Iyengar, S., Blahnik, K., Rinn, J. L., Chang, H. Y., Green, R., & Farnham, P. J. (2007) · PLoS Genetics · doi:10.1371/journal.pgen.0030089 · Cited by 178 · cited 2× · see citing works
“Multiple reports have described the ratio of human L1s that are truncated, we used these reports as the basis for adjusting raw read depth to normalized read depth 53,54 .”
Mao, Z., Tian, X., Van Meter, M., Ke, Z., Gorbunova, V., & Seluanov, A. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1200583109 · Cited by 176 · cited 1× · see citing works
“Additional factors that may contribute to reduced SIRT6-mediated L1 silencing are declining levels of nuclear NAD+ 56 and lower levels of SIRT6 in senescent cells 57 .”
Self-citationThe Role of Transposable Elements in Health and Diseases of the Central Nervous System
Reilly, M. T., Faulkner, G. J., Dubnau, J., Ponomarev, I., & Gage, F. H. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.3369-13.2013 · Cited by 175 · cited 1× · see citing works
“Consistent with this observation, L1 activity has been implicated in a variety of age-related disorders 12 , including cancer 7,13 and neurodegeneration 14,15 .”
Li, X., Lee, Y.-K., Jeng, J.-C., Yen, Y., Schultz, D. C., Shih, H.-M., & Ann, D. K. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m706912200 · Cited by 168 · cited 2× · see citing works
“Finally, it is worth noting that post-translational modification of KAP1 plays a critical role in determining which cellular context the protein will function in; for example sumoylated KAP1 promotes regulation of gene expression, while phosphorylated KAP1 promotes DNA repair 41,42 .”
White, D., Rafalska-Metcalf, I. U., Ivanov, A. V., Corsinotti, A., Peng, H., Lee, S.-C., Trono, D., Janicki, S. M., & Rauscher, F. J. (2012) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-11-0134 · Cited by 152 · cited 2× · see citing works
“Finally, it is worth noting that post-translational modification of KAP1 plays a critical role in determining which cellular context the protein will function in; for example sumoylated KAP1 promotes regulation of gene expression, while phosphorylated KAP1 promotes DNA repair 41,42 .”
Retrotransposition is associated with genome instability during chronological aging
Maxwell, P. H., Burhans, W. C., & Curcio, M. J. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1100271108 · Cited by 132 · cited 1× · see citing works
“Several reports have implicated retrotransposons as drivers of phenotypes associated with the aging process 11,33,34 .”
Kaneda, M., Hirasawa, R., Chiba, H., Okano, M., Li, E., & Sasaki, H. (2010) · Genes to Cells · doi:10.1111/j.1365-2443.2009.01374.x · Cited by 103 · see citing works
Dynamic Chromatin Localization of Sirt6 Shapes Stress- and Aging-Related Transcriptional Networks
Kawahara, T. L. A., Rapicavoli, N. A., Wu, A. R., Qu, K., Quake, S. R., & Chang, H. Y. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002153 · Cited by 101 · cited 1× · see citing works
“To understand the extent to which KAP1 and SIRT6 co-occupied promoters, we downloaded and compared all well-annotated target genes for each sequence from publically available datasets 54,55 .”
(1998) · Experimental Gerontology · doi:10.1016/s0531-5565(98)00037-0 · Cited by 82 · cited 1× · see citing works
“This relocalization of SIRT6 in response to stress is reminiscent of the ‘redistribution of chromatin modifier theory of aging’ 43,44 , which predicts that while mobilization of chromatin modifying elements in response to stress-stimuli is adaptive in young organisms, constitutive redistribution of…”
Repairing split ends: SIRT6, mono-ADP ribosylation and DNA repair
Van Meter, M., Mao, Z., Gorbunova, V., & Seluanov, A. (2011) · Aging · doi:10.18632/aging.100389 · Cited by 80 · cited 1× · see citing works
“SIRT6 is known to rapidly relocalize to DNA damage sites in response to oxidative stress 19,36 .”
Self-citationRetrotransposon activation contributes to fragile X premutation rCGG-mediated neurodegeneration
Tan, H., Qurashi, A., Poidevin, M., Nelson, D. L., Li, H., & Jin, P. (2012) · Human Molecular Genetics · doi:10.1093/hmg/ddr437 · Cited by 78 · cited 1× · see citing works
“Consistent with this observation, L1 activity has been implicated in a variety of age-related disorders 12 , including cancer 7,13 and neurodegeneration 14,15 .”
St. Laurent, G., Hammell, N., & McCaffrey, T. A. (2010) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2010.03.008 · Cited by 68 · cited 2× · see citing works
“Several reports have implicated retrotransposons as drivers of phenotypes associated with the aging process 11,33,34 .”
Zhong, X., Zhang, H., Zhao, Y. J., Sun, Q., Hu, Y., Peng, H., & Zhou, D. (2013) · PLoS ONE · doi:10.1371/journal.pone.0066807 · Cited by 58 · cited 1× · see citing works
“It is also worth noting that Sirtuin 1 (SIRT1), another mammalian member of the siruin gene family, has been implicated in silencing repetitive elements, including retrotransposons and major satellite repeats 43,48 .”
Aging genomes: A necessary evil in the logic of life
Vijg, J. (2014) · BioEssays · doi:10.1002/bies.201300127 · Cited by 25 · cited 1× · see citing works
“DNA damage is more abundant in old cells and tissues 37,38 .”
The possible roles of human Alu elements in aging
Mustafina, O. E. (2013) · Frontiers in Genetics · doi:10.3389/fgene.2013.00096 · Cited by 19 · cited 1× · see citing works
“Several reports have implicated retrotransposons as drivers of phenotypes associated with the aging process 11,33,34 .”
SIRT6: A Promising Target for Cancer Prevention and Therapy
Meter, M. V., Gorbunova, V. A., & Seluanov, A. (2014) · Advances in experimental medicine and biology · doi:10.1007/978-1-4471-6458-6_9 · Cited by 14 · see citing works
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Ten things you should know about transposable elements
Bourque, G., Burns, K. H., Gehring, M., Gorbunova, V., Seluanov, A., Hammell, M., Imbeault, M., Izsvák, Z., Levin, H. L., Macfarlan, T. S., et al. (2018) · Genome Biology · doi:10.1186/s13059-018-1577-z · Cited by 1,430 · see citing works
Self-citationRegulatory activities of transposable elements: from conflicts to benefits
Chuong, E. B., Elde, N. C., & Feschotte, C. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.139 · Cited by 1,343 · see citing works
L1 drives IFN in senescent cells and promotes age-associated inflammation
De Cecco, M., Ito, T., Petrashen, A. P., Elias, A. E., Skvir, N. J., Criscione, S. W., Caligiana, A., Brocculi, G., Adney, E. M., Boeke, J. D., et al. (2019) · Nature · doi:10.1038/s41586-018-0784-9 · Cited by 1,255 · see citing works
Self-citationPal, S., & Tyler, J. K. (2016) · Science Advances · doi:10.1126/sciadv.1600584 · Cited by 860 · see citing works
“Accordingly, SIRT6-mediatedmono–ADP-ribosylation of KAP1 was shown to promote its interaction with HP1 and the packaging of L1 LINE elements into repressive heterochromatin (72).”
BackgroundSlowing ageing by design: the rise of NAD+ and sirtuin-activating compounds
Bonkowski, M. S., & Sinclair, D. A. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.93 · Cited by 834 · see citing works
Roles for retrotransposon insertions in human disease
Hancks, D. C., & Kazazian, H. H. (2016) · Mobile DNA · doi:10.1186/s13100-016-0065-9 · Cited by 670 · see citing works
Epigenetic regulation of ageing: linking environmental inputs to genomic stability
Benayoun, B. A., Pollina, E. A., & Brunet, A. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm4048 · Cited by 610 · see citing works
LINE1 Derepression in aged wild-type and SIRT6-deficient mice drives inflammation
Simon, M., Van Meter, M., Ablaeva, J., Ke, Z., Gonzalez, R. S., Taguchi, T., De Cecco, M., Leonova, K. I., Kogan, V., Helfand, S. L., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.02.014 · Cited by 498 · see citing works
Self-citationThe quest to slow ageing through drug discovery
Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0067-7 · Cited by 468 · see citing works
Restricting retrotransposons: a review
Goodier, J. L. (2016) · Mobile DNA · doi:10.1186/s13100-016-0070-z · Cited by 436 · see citing works
The ageing epigenome and its rejuvenation
Zhang, W., Qu, J. T., Liu, G., & Belmonte, J. C. I. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0204-5 · Cited by 472 · see citing works
The role of retrotransposable elements in ageing and age-associated diseases
Gorbunova, V., Seluanov, A., Mita, P., McKerrow, W., Fenyö, D., Boeke, J. D., Linker, S. B., Gage, F. H., Kreiling, J. A., Petrashen, A. P., et al. (2021) · Nature · doi:10.1038/s41586-021-03542-y · Cited by 457 · see citing works
Self-citationCai, Y., Song, W., Li, J., Jing, Y., Liang, C., Zhang, L., Zhang, X., Zhang, W., Liu, B., An, Y., et al. (2022) · Science China Life Sciences · doi:10.1007/s11427-022-2161-3 · Cited by 436 · see citing works
Resurrection of endogenous retroviruses during aging reinforces senescence
Liu, X., Liu, Z., Wu, Z., Ren, J., Fan, Y., Sun, L., Cao, G., Niu, Y., Zhang, B., Ji, Q., et al. (2023) · Cell · doi:10.1016/j.cell.2022.12.017 · Cited by 390 · see citing works
Benayoun, B. A., Pollina, E. A., Singh, P. P., Mahmoudi, S., Harel, I., Casey, K. M., Dulken, B. W., Kundaje, A., & Brunet, A. (2019) · Genome Research · doi:10.1101/gr.240093.118 · Cited by 360 · see citing works
SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection
D’Onofrio, N., Servillo, L., & Balestrieri, M. L. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7178 · Cited by 389 · see citing works
Nuclear DNA damage signalling to mitochondria in ageing
Fang, E. F., Scheibye-Knudsen, M., Chua, K. F., Mattson, M. P., Croteau, D. L., & Bohr, V. A. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.14 · Cited by 387 · see citing works
DNA damage and repair in age-related inflammation
Zhao, Y., Simon, M. A., Seluanov, A., & Gorbunova, V. A. (2022) · Nature reviews. Immunology · doi:10.1038/s41577-022-00751-y · Cited by 393 · see citing works
Self-citationThe Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy
Guo, L., Tian, Y., & Zhu, W. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.576946 · Cited by 358 · see citing works
SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2
Pan, H., Guan, D., Liu, X., Li, J., Wang, L., Wu, J., Zhou, J., Zhang, W., Ren, R., Zhang, W., et al. (2016) · Cell Research · doi:10.1038/cr.2016.4 · Cited by 334 · see citing works
Epigenetic changes during aging and their reprogramming potential
Kane, A. E., & Sinclair, D. A. (2019) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2019.1570075 · Cited by 283 · see citing works
“…recently, however, LINE-1 RNA has been readily detected in the cytoplasm of aged mouse cells and appears to play a major role in hyper-activating the inflammatory response in older animals and even dictating lifespan (Gorbunova et al. 2014, J. Sedivy. personal communication; van Meter et al. 2014).”
BackgroundInfluentialCytoplasmic DNA: sources, sensing, and role in aging and disease
Miller, K. N., Victorelli, S. G., Salmonowicz, H., Dasgupta, N., Liu, T., Passos, J. F., & Adams, P. D. (2021) · Cell · doi:10.1016/j.cell.2021.09.034 · Cited by 288 · see citing works
Cellular and epigenetic drivers of stem cell ageing
Ermolaeva, M., Neri, F., Ori, A., & Rudolph, K. L. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0020-3 · Cited by 272 · see citing works
The complexity of TRIM28 contribution to cancer
Czerwińska, P., Mazurek, S., & Wiznerowicz, M. (2017) · Journal of Biomedical Science · doi:10.1186/s12929-017-0374-4 · Cited by 272 · see citing works
Functions of the sirtuin deacylase SIRT5 in normal physiology and pathobiology
Kumar, S., & Lombard, D. B. (2018) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2018.1458071 · Cited by 264 · see citing works
“…deacetylase (Michishita et al. 2008; Kaidi et al. 2010; Tasselli et al. 2017), ADP-ribosyltransferase (Liszt et al. 2005; Mao et al. 2011; Van Meter et al. 2014) and long-chain deacylase (Feldman et al. 2013; Wang et al. 2016) activities, and SIRT7 mediates deacetylation (Barber et al. 2012;…”
SIRT6: Novel Mechanisms and Links to Aging and Disease
Tasselli, L., Zheng, W., & Chua, K. F. (2016) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2016.10.002 · Cited by 267 · see citing works
“What are the ‘ribosylome’ or ‘fatty-acylomes’ that are regulated by such modifications? How do the modifications affect protein function, cellular signaling, or epigenetic networks? How are these or other SIRT6-dependent modifications linked to cellular energy states or metabolic fluctuations? In addition, can new sep…”
InfluentialSirtuins and Their Roles in Brain Aging and Neurodegenerative Disorders
Jęśko, H. M., Wencel, P. L., Strosznajder, R. P., & Strosznajder, J. B. (2016) · Neurochemical Research · doi:10.1007/s11064-016-2110-y · Cited by 262 · see citing works
“Likewise, in the aged brain diminished SIRT6 binding could lead to genomic instability [103].”
BackgroundLüscher, B., Bütepage, M., Eckei, L., Krieg, S., Verheugd, P., & Shilton, B. H. (2017) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00122 · Cited by 258 · see citing works
Sirtuin regulation in aging and injury
Poulose, N., & Raju, R. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.08.017 · Cited by 236 · see citing works
SIRT6, a Mammalian Deacylase with Multitasking Abilities
Chang, A. R., Ferrer, C. M., & Mostoslavsky, R. (2019) · Physiological Reviews · doi:10.1152/physrev.00030.2018 · Cited by 236 · see citing works
Sirtuins, epigenetics and longevity
Wątroba, M., Dudek, I., Skoda, M., Stangret, A., Rzodkiewicz, P., & Szukiewicz, D. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.08.001 · Cited by 221 · see citing works
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“TE activation has been observed with age in mice (8, 12), as well as C.”
BackgroundTasselli, L., Xi, Y., Zheng, W., Tennen, R. I., Odrowaz, Z., Simeoni, F., Li, W., & Chua, K. F. (2016) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3202 · Cited by 213 · see citing works
How retrotransposons shape genome regulation
Mita, P., & Boeke, J. D. (2016) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2016.01.001 · Cited by 205 · see citing works
“G9a [68], Eset/Setdb1 [69,70 ], KAP1/ZNF proteins [37 ,71] and Lsd1/KDM1A [72] repress retrotransposons in embryonic stem (ES) cells.”
Revisiting the Relationship between Transposable Elements and the Eukaryotic Stress Response
Horváth, V., Merenciano, M., & González, J. (2017) · Trends in Genetics · doi:10.1016/j.tig.2017.08.007 · Cited by 202 · see citing works
“Under stress conditions and also during aging, SIRT6 relocates to DNA damage sites, and as a consequence LINE-1s are no longer kept in a heterochromatic state and are thus transcribed [34], thereby indirectly leading to the activation of LINE-1 elements.”
BackgroundAhmed, A. S. I., Sheng, M. H. ‐., Wasnik, S., Baylink, D. J., & Lau, K. ‐. W. (2017) · World Journal of Experimental Medicine · doi:10.5493/wjem.v7.i1.1 · Cited by 202 · see citing works
Emerging roles of SIRT6 in human diseases and its modulators
Liu, G., Chen, H., Liu, H., Zhang, W., & Zhou, J. (2020) · Medicinal Research Reviews · doi:10.1002/med.21753 · Cited by 177 · see citing works
“SIRT6 was revealed to bind to 5′‐untranslated region (5′‐UTR) of long interspersed element 1 (L1) loci and mono‐ADP ribosylate the nuclear corepressor protein, KAP1, and thus suppress the activity of L1 retrotransposon, which may be relevant in the course of aging.(20) In addition, SIRT6 has been shown to ADP‐ribosyla…”
BackgroundSIRT3 consolidates heterochromatin and counteracts senescence
Diao, Z., Ji, Q., Wu, Z., Zhang, W., Cai, Y., Wang, Z., Hu, J., Liu, Z., Wang, Q., Bi, S., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab161 · Cited by 171 · see citing works
SIRT7 antagonizes human stem cell aging as a heterochromatin stabilizer
Bi, S., Liu, Z., Wu, Z., Wang, Z., Liu, X., Wang, S., Ren, J., Yao, Y., Zhang, W., Song, M., et al. (2020) · Protein & Cell · doi:10.1007/s13238-020-00728-4 · Cited by 160 · see citing works
SIRT6 in Aging, Metabolism, Inflammation and Cardiovascular Diseases
Guo, Z., Li, P., Ge, J., & Li, H. (2022) · Aging and Disease · doi:10.14336/ad.2022.0413 · Cited by 160 · see citing works
“KAP1 Promotes SIRT6-KAP1-HP1α complex formation and heterochromatin packaging to decrease LINE1 expression Inhibits genomic instability and senescence[33]”
BackgroundInfluentialTransposable Elements, Inflammation, and Neurological Disease
Saleh, A., Macia, A., & Muotri, A. R. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.00894 · Cited by 149 · see citing works
“SNERV1/2 bind to the gp70-associated loci, Sgp3, and recruit KAP1 to repress transcription.”
BackgroundFouché, S., Badet, T., Oggenfuss, U., Plissonneau, C., Francisco, C. S., & Croll, D. (2019) · Molecular Biology and Evolution · doi:10.1093/molbev/msz216 · Cited by 134 · see citing works
Stabilizing heterochromatin by DGCR8 alleviates senescence and osteoarthritis
Deng, L., Ren, R., Liu, Z., Song, M., Li, J., Wu, Z., Ren, X., Fu, L., Li, W., Zhang, W., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10831-8 · Cited by 138 · see citing works
The Chromatin Landscape of Cellular Senescence
Criscione, S. W., Teo, Y. V., & Neretti, N. (2016) · Trends in Genetics · doi:10.1016/j.tig.2016.09.005 · Cited by 137 · see citing works
“The depletion of SIRT6 at retrotransposons is triggered by genotoxic stress, however, the molecular mechanism for depletion is still unclear [88].”
BackgroundpiRNA involvement in genome stability and human cancer
Moyano, M., & Stefani, G. (2015) · Journal of Hematology & Oncology · doi:10.1186/s13045-015-0133-5 · Cited by 135 · see citing works
Lamin A Is an Endogenous SIRT6 Activator and Promotes SIRT6-Mediated DNA Repair
Ghosh, S., Liu, B., Wang, Y., Hao, Q., & Zhou, Z. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.10.006 · Cited by 129 · see citing works
“…from PARP1, SIRT6 1396 Cell Reports 13, 1396–1406, November 17, 2015 ª2015 The Au has been reported to mediate mono-ADP ribosylation of the nuclear corepressor Kap1, thereby aiding in the packaging of L1 retrotransposons into transcriptionally repressive heterochromatin (Van Meter et al., 2014).”
Backgroundpatternize: An R package for quantifying colour pattern variation
Belleghem, S. M. V., Papa, R., Ortiz‐Zuazaga, H., et al. (2017) · Methods in Ecology and Evolution · doi:10.1111/2041-210x.12853 · Cited by 133 · see citing works
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“The MEFs were differentiated into adipocytes as described (23).”
BackgroundMeter, M. V., Simon, M. A., Tombline, G., May, A., Morello, T. D., Hubbard, B. P., Bredbenner, K., Park, R., Sinclair, D. A., Bohr, V. A., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.08.006 · Cited by 130 · see citing works
“Modification of Kap1 by SIRT6 promotes silencing of L1 retrotransposons (Van Meter et al., 2014).”
BackgroundSelf-citationThe genetics of human longevity: an intricacy of genes, environment, culture and microbiome
Dato, S., Rose, G., Crocco, P., Monti, D., Garagnani, P., Franceschi, C., & Passarino, G. (2017) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2017.03.011 · Cited by 134 · see citing works
The Broad-Spectrum Antiviral Protein ZAP Restricts Human Retrotransposition
Goodier, J. L., Pereira, G., Cheung, L. E., Rose, R. J., & Kazazian, H. H. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1005252 · Cited by 131 · see citing works
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Incorporation of a nucleoside analog maps genome repair sites in postmitotic human neurons
Reid, D. A., Reed, P. J., Schlachetzki, J. C. M., Nitulescu, I. I., Chou, G., Tsui, E. C., Jones, J. R., Chandran, S., Lu, A. T., McClain, C. A., et al. (2021) · Science · doi:10.1126/science.abb9032 · Cited by 121 · see citing works
The Current State of NAD+‐Dependent Histone Deacetylases (Sirtuins) as Novel Therapeutic Targets
Schiedel, M., Robaa, D., Rumpf, T., Sippl, W., & Jung, M. (2017) · Medicinal Research Reviews · doi:10.1002/med.21436 · Cited by 122 · see citing works
Transposable Elements: A Common Feature of Neurodevelopmental and Neurodegenerative Disorders
Jönsson, M. E., Garza, R., Johansson, P. A., & Jakobsson, J. (2020) · Trends in Genetics · doi:10.1016/j.tig.2020.05.004 · Cited by 122 · see citing works
“Loss of SIRT6, either via experimental modeling or through age-dependent downregulation, results in increased levels of LINE-1-derived RNA and DNA [92,93].”
BackgroundDiseases of the nERVous system: retrotransposon activity in neurodegenerative disease
Tam, O. H., Ostrow, L. W., & Hammell, M. (2019) · Mobile DNA · doi:10.1186/s13100-019-0176-1 · Cited by 118 · see citing works
Wu, Z., Qu, J., & Liu, G.-H. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00775-3 · Cited by 118 · see citing works
“32,51–53), and the regulators of the RNA N 6 -methyladenosine (m 6 A) modification such as METTL3 (m 6 A writer) 54,55 , FTO (eraser) 56,57 and YTHDC1 (reader) 58,59 , the canonical microRNA processing factor DGCR8 (ref.”
Stabilization of heterochromatin by CLOCK promotes stem cell rejuvenation and cartilage regeneration
Liang, C., Liu, Z., Song, M., Li, W., Wu, Z., Wang, Z., Wang, Q., Wang, S., Yan, K., Sun, L., et al. (2020) · Cell Research · doi:10.1038/s41422-020-0385-7 · Cited by 117 · see citing works
Micromanaging aerobic respiration and glycolysis in cancer cells
Orang, A., Petersen, J., McKinnon, R. A., & Michael, M. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.01.014 · Cited by 115 · see citing works
L1 Mosaicism in Mammals: Extent, Effects, and Evolution
Faulkner, G. J., & Garcia-Perez, J. L. (2017) · Trends in Genetics · doi:10.1016/j.tig.2017.07.004 · Cited by 110 · see citing works
Sirtuin 6: linking longevity with genome and epigenome stability
Korotkov, A., Seluanov, A., & Gorbunova, V. A. (2021) · Trends in Cell Biology · doi:10.1016/j.tcb.2021.06.009 · Cited by 114 · see citing works
Self-citationRegulation of Glucose Metabolism by NAD+ and ADP-Ribosylation
Hopp, A.-K., Grüter, P., & Hottiger, M. O. (2019) · Cells · doi:10.3390/cells8080890 · Cited by 107 · see citing works
Nelson, D. M., Jaber‐Hijazi, F., Cole, J. J., Robertson, N., Pawlikowski, J. S., Norris, K., Criscione, S. W., Pchelintsev, N. A., Piscitello, D., Stong, N., et al. (2016) · Genome biology · doi:10.1186/s13059-016-1017-x · Cited by 103 · see citing works
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Destabilizing heterochromatin by APOE mediates senescence
Zhao, H., Ji, Q., Wu, Z., Wang, S., Ren, J., Yan, K., Wang, Z., Hu, J., Chu, Q., Hu, H., et al. (2022) · Nature Aging · doi:10.1038/s43587-022-00186-z · Cited by 104 · see citing works
Akter, R., Afrose, A., Rahman, M. R., Chowdhury, R., Nirzhor, S. S. R., Khan, R. I., & Kabir, M. T. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22084180 · Cited by 103 · see citing works
Intracellular Mono-ADP-Ribosylation in Signaling and Disease
Bütepage, M., Eckei, L., Verheugd, P., & Lüscher, B. (2015) · Cells · doi:10.3390/cells4040569 · Cited by 93 · see citing works
“This activates the L1 retrotransposons, which can ultimately contribute to genomic instability and age-related diseases such as cancer [50].”
BackgroundInfluentialLiberale, L., Gaul, D. S., Akhmedov, A. T., Bonetti, N. R., Nageswaran, V., Costantino, S., Pahla, J., Weber, J., Fehr, V., Vdovenko, D., et al. (2019) · European Heart Journal · doi:10.1093/eurheartj/ehz712 · Cited by 95 · see citing works
The epigenetic alterations of endogenous retroelements in aging
Cardelli, M. (2018) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2018.02.002 · Cited by 91 · see citing works
Engrailed homeoprotein blocks degeneration in adult dopaminergic neurons through LINE‐1 repression
de Thé, F.-X. B., Rekaik, H., Pezé-Heidsieck, E., Massiani-Beaudoin, O., Joshi, R. L., Fuchs, J., & Prochiantz, A. (2018) · The EMBO Journal · doi:10.15252/embj.201797374 · Cited by 95 · see citing works
“Direct regulation was shown for p53 and SIRT6, two proteins involved in the regulation of aging (Van Meter et al , 2014; Wylie et al , 2016) and it must be noted that L1 repression by SIRT6 fails with age and stress (Van Meter et al , 2014).”
InfluentialGenetics of human longevity within an eco-evolutionary nature-nurture framework
Giuliani, C., Garagnani, P., & Franceschi, C. (2018) · Circulation Research · doi:10.1161/circresaha.118.312562 · Cited by 92 · see citing works
Sensing of transposable elements by the antiviral innate immune system
Gázquez-Gutiérrez, A., Witteveldt, J., Heras, S. R., & Macías, S. (2021) · RNA · doi:10.1261/rna.078721.121 · Cited by 92 · see citing works
“Alternatively, LINE-1 cDNA could also be recognized by cGAS in the nucleus, as a significant proportion of this sensor has been found in the nuclear compartment of specific cell types (Xia et al. 2018; Gentili et al. 2019; Volkman et al. 2019).”
BackgroundThe complex role of SIRT6 in carcinogenesis
Lerrer, B., Gertler, A. A., & Cohen, H. Y. (2015) · Carcinogenesis · doi:10.1093/carcin/bgv167 · Cited by 91 · see citing works
Repetitive elements as a transcriptomic marker of aging: Evidence in multiple datasets and models
LaRocca, T. J., Cavalier, A. N., & Wahl, D. (2020) · Aging Cell · doi:10.1111/acel.13167 · Cited by 78 · see citing works
Exaptation of transposable element coding sequences
Joly‐Lopez, Z., & Bureau, T. E. (2018) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2018.02.011 · Cited by 90 · see citing works
Retrotransposons shape species-specific embryonic stem cell gene expression
Robbez‐Masson, L., & Rowe, H. M. (2015) · Retrovirology · doi:10.1186/s12977-015-0173-5 · Cited by 89 · see citing works
Haws, S. A., Yu, D., Ye, C., Wille, C. K., Nguyen, L. C., Krautkramer, K. A., Tomasiewicz, J. L., Yang, S. E., Miller, B. R., Liu, W. H., et al. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.03.004 · Cited by 90 · see citing works
DNA double strand break repair, aging and the chromatin connection
Gorbunova, V., & Seluanov, A. (2016) · Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis · doi:10.1016/j.mrfmmm.2016.02.004 · Cited by 87 · see citing works
“Similarly to SIRT1, DNA damage leads to redistribution of SIRT6 on chromatin, where SIRT6 moves from LINE1 promoters to DNA break sites leading to derepression of LINE1 elements [66].”
BackgroundSelf-citationWei, C., Cheng, J., Zhou, B., et al. (2016) · Scientific Reports · doi:10.1038/srep29822 · Cited by 87 · see citing works
Emerging Therapeutic Potential of SIRT6 Modulators
Fiorentino, F., Mai, A., & Rotili, D. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00601 · Cited by 93 · see citing works
Type I interferons and related pathways in cell senescence
Frisch, S. M., & MacFawn, I. (2020) · Aging Cell · doi:10.1111/acel.13234 · Cited by 85 · see citing works
“SIRT6 knockout mice show a progeria phenotype accompanied by sterile inflammation, an excess of cell senescence markers, stem cell exhaustion, and LINE-1 transcription, as SIRT6 normally represses the latter (Van Meter et al., 2014; Mostoslavsky et al., 2006).”
BackgroundKRAB-ZFP Transcriptional Regulators Acting as Oncogenes and Tumor Suppressors: An Overview
Sobocińska, J., Molenda, S., Machnik, M., & Oleksiewicz, U. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22042212 · Cited by 85 · see citing works
“Interestingly, upon aging and in response to DNA damage (the processes linked to cancer development), SIRT6 detaches from L1 sequences, which disrupts the KAP1-corepressor complex, and activates L1 expression [55].”
BackgroundSIRT6 is a key regulator of mitochondrial function in the brain
Smirnov, D., Eremenko, E., Stein, D., Kaluski, S., Jasińska, W., Cosentino, C., Martínez-Pastor, B., Brotman, Y., Mostoslavsky, R., Khrameeva, E. E., et al. (2023) · Cell Death and Disease · doi:10.1038/s41419-022-05542-w · Cited by 87 · see citing works
SIRT6 promotes transcription of a subset of NRF2 targets by mono-ADP-ribosylating BAF170
Rezazadeh, S., Yang, D. X., Tombline, G., Simon, M. A., Regan, S. P., Seluanov, A., & Gorbunova, V. A. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz528 · Cited by 80 · see citing works
“These include PARP1 (13), modification of which promotes DNA repair under oxidative stress, and Kap1 which is involved in silencing of LINE1 elements (14).”
BackgroundSelf-citationLINE-1 retrotransposons drive human neuronal transcriptome complexity and functional diversification
Garza, R., Atacho, D. A. M., Adami, A., Gerdes, P., Vinod, M., Hsieh, P., Karlsson, O., Horváth, V., Johansson, P. A., Pandiloski, N., et al. (2023) · Science Advances · doi:10.1126/sciadv.adh9543 · Cited by 83 · see citing works
“It is well established that DNA methylation patterns change with age and there are emerging studies linking age-related epigenetic changes to activation of TE expression ( 55 – 57 ).”
Activation of endogenous retroviruses during brain development causes an inflammatory response
Jönsson, M. E., Garza, R., Sharma, Y., Petri, R., Södersten, E., Johansson, J. G., Johansson, P. A., Atacho, D. A., Pircs, K., Madsen, S., et al. (2021) · The EMBO Journal · doi:10.15252/embj.2020106423 · Cited by 80 · see citing works
“…inhibition of DNMTs, aging or by genetic alterations results in an interferon response through the recognition of double-stranded RNA or other TE-derived nucleic acids (Van Meter et al , 2014; Lim et al , 2015; Roulois et al , 2015; Thomas et al , 2017; Ahmad et al , 2018; De Cecco et al , 2019).”
SIRT7 mediates L1 elements transcriptional repression and their association with the nuclear lamina
Vazquez, B. N., Thackray, J. K., Simonet, N. G., Chahar, S., Kane-Goldsmith, N., Newkirk, S. J., Lee, S., Xing, J., Verzi, M. P., An, W., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz519 · Cited by 79 · see citing works
“In differentiated mammalian cells, only SIRT6 has been associated with L1 transcriptional repression (92).”
BackgroundThe Y chromosome may contribute to sex-specific ageing in Drosophila
Brown, E. J., Nguyen, A. H., & Bachtrog, D. (2020) · Nature Ecology & Evolution · doi:10.1038/s41559-020-1179-5 · Cited by 80 · see citing works
The Two-Faced Role of SIRT6 in Cancer
Fiorentino, F., Carafa, V., Favale, G., Altucci, L., Mai, A., & Rotili, D. (2021) · Cancers · doi:10.3390/cancers13051156 · Cited by 79 · see citing works
“Here, it mono-ADP-ribosylates the nuclear corepressor KAP1, thereby facilitating its interaction with the heterochromatin factor HP1α and ensuring genome stability through L1s packaging into transcriptionally inaccessible heterochromatin [22].”
BackgroundThe role of the dynamic epigenetic landscape in senescence: orchestrating SASP expression
Dasgupta, N., Arnold, R., Equey, A., Gandhi, A., & Adams, P. D. (2024) · npj Aging · doi:10.1038/s41514-024-00172-2 · Cited by 86 · see citing works
“The enzyme Sirtuin 6 (SIRT6), known for its protein deacetylase and mono-ADP ribosyltransferase activities, is also enriched in the 5 ′ UTR of L1 loci 137 .”
BackgroundInfluentialRetrotransposon-induced mosaicism in the neural genome
Bodea, G. O., McKelvey, E. G. Z., & Faulkner, G. J. (2018) · Open Biology · doi:10.1098/rsob.180074 · Cited by 76 · see citing works
Long Non-Coding RNAs in Neuronal Aging
Fernandes, D. P., Bitar, M., Jacobs, F. M. J., & Barry, G. (2018) · Non-Coding RNA · doi:10.3390/ncrna4020012 · Cited by 75 · see citing works
“Interestingly, mounting evidence from studies in the senescence and aging of multiple organisms suggests that alterations in the activity of TEs-associated repressors [146,147], and the loss of heterochromatin [148,149], underlie TE activation in aging [150,151].”
Chénais, B. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052551 · Cited by 75 · see citing works
“In addition, the longevity regulatory protein, SIRT6, appeared as a potent silencer of LINE-1 in mice, and its depletion during aging, or following DNA damage, allows the reactivation of LINE-1 [136].”
BackgroundLINE‐1 retrotransposons in healthy and diseased human brain
Suarez, N. A., Macia, Á., & Muotri, A. R. (2017) · Developmental Neurobiology · doi:10.1002/dneu.22567 · Cited by 74 · see citing works
A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A
Simon, M. A., Yang, J., Gigas, J., Earley, E. J., Hillpot, E. C., Zhang, L. J., Zagorulya, M., Tombline, G., Gilbert, M. B., Yuen, S. L., et al. (2022) · The EMBO Journal · doi:10.15252/embj.2021110393 · Cited by 68 · see citing works
“…the ribosylation of KAP1 by SIRT6 and subsequent recruitment to transposable elements plays a critical role in silencing these opportunistic elements, which have been linked to age-related sterile inflammation and DNA damage (Van Meter et al , 2014; De Cecco et al , 2019; Simon et al , 2019).”
Self-citationPhosphorylation of ORF1p is required for L1 retrotransposition
Cook, P. R., Jones, C. E., & Furano, A. V. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1416869112 · Cited by 70 · see citing works
“In addition to its normal and evolutionary relevant replication niche in germline and early embryonic cells (26, 27, 69–71), L1 also can be active in some somatic cells, including certain tumors and neuronal progenitor cells (19, 20, 23), as well as a consequence of aging (72).”
BackgroundTransposable Elements: Major Players in Shaping Genomic and Evolutionary Patterns
Romano, N. C., & Fanti, L. (2022) · Cells · doi:10.3390/cells11061048 · Cited by 76 · see citing works
Transposable elements as new players in neurodegenerative diseases
Ravel‐Godreuil, C., Znaidi, R., Bonnifet, T., Joshi, R. L., & Fuchs, J. (2021) · FEBS Letters · doi:10.1002/1873-3468.14205 · Cited by 67 · see citing works
The mechanism of ageing: primary role of transposable elements in genome disintegration
Sturm, Á., Ivics, Z., & Vellai, T. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1896-0 · Cited by 69 · see citing works
“Moreover, repression of LINE1 by SIRT6 into transcriptionally inactive heterochromatin fails to occur during the course of ageing [50].”
Background
- Authors
- Van Meter, M., Kashyap, M., Rezazadeh, S., Geneva, A. J., Morello, T. D., Seluanov, A., & Gorbunova, V.
- Affiliations
- University of Rochester (US)
- Corresponding author
- Seluanov, Andrei
- Gorbunova, Vera
- Venue
- Nature Communications
- Published
- 2014-09-23
- Volume
- 5
- Issue
- 1
- Pages
- 5011-5011
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4185372
- OpenAlex
- W2064802388
- Cited by
- 455
- References
- 57
- Citations by year
- 2026: 32 · 2025: 53 · 2024: 48 · 2023: 27 · 2022: 49 · 2021: 41 · 2020: 36 · 2019: 41 · 2018: 25 · 2017: 29 · 2016: 35 · 2015: 20 · 2014: 1
- FWCI
- 31.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- SIRT6, LINE-1 retrotransposons, KAP1, mono-ADP-ribosylation, heterochromatin, HP1α, transposable elements, aging
- MeSH terms
- Tripartite Motif-Containing Protein 28, Aging, Animals, Heterochromatin, Luciferases, Nuclear Proteins, Repressor Proteins, Stress, Physiological, Sulfites
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-20.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-20.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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