Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining
Open accessAbstract
DNA double-strand break (DSB) repair occurs within chromatin and can be modulated by chromatin-modifying enzymes. Here we identify the related human histone deacetylases HDAC1 and HDAC2 as two participants in the DNA-damage response. We show that acetylation of histone H3 Lys56 (H3K56) was regulated by HDAC1 and HDAC2 and that HDAC1 and HDAC2 were rapidly recruited to DNA-damage sites to promote hypoacetylation of H3K56. Furthermore, HDAC1- and 2-depleted cells were hypersensitive to DNA-damaging agents and showed sustained DNA-damage signaling, phenotypes that reflect defective DSB repair, particularly by nonhomologous end-joining (NHEJ). Collectively, these results show that HDAC1 and HDAC2 function in the DNA-damage response by promoting DSB repair and thus provide important insights into the radio-sensitizing effects of HDAC inhibitors that are being developed as cancer therapies.
AI snapshot
Written from the paper’s full text.
TL;DR
HDAC1 and HDAC2 are recruited to DNA-damage sites, where they promote H3K56 and H4K16 hypo-acetylation and are required for efficient DNA double-strand break repair, predominantly non-homologous end-joining (NHEJ). Their depletion causes hypersensitivity to DNA-damaging agents and sustained DNA-damage signaling, linking HDAC1/2 function to the radio-sensitizing effects of HDAC inhibitors.
Key findings
- HDAC1 and HDAC2, but not HDAC3 or HDAC8, localized to laser-induced DNA-damage sites; accumulation occurred within 5 minutes and was no longer visible after 30 minutes.
- HDAC1/2 depletion caused hyper-acetylation of H3K56 and H4K16, and recombinant HDAC1 deacetylated these sites on calf histones in vitro, suggesting they are likely direct targets.
- HDAC1/2-depleted cells were hypersensitive to ionizing radiation and phleomycin, showed sustained γH2AX, CHK1, CHK2 and p53 phosphorylation, and had markedly impaired repair of IR- and phleomycin-induced DSBs by comet assay.
- HDAC1/2 depletion produced a modest reduction in homologous recombination and a major defect in NHEJ; it also increased DNA-PKcs autophosphorylation (S2056p) and ATM-mediated phosphorylation (T2609p), and enhanced Ku70/Artemis persistence at damage sites.
Methods
- Cell-based study using human U2OS, HeLa and human diploid fibroblast cells, including a U2OS line with 4-OHT-inducible AsiSI-ER to generate site-specific DSBs.
- HDAC1/2 function was tested by siRNA depletion, siRNA-resistant HDAC1 rescue, and Class I/II HDAC inhibitors TSA and NaB, with Sirtuin inhibition by nicotinamide and SIRT1/SIRT2 depletion as comparisons.
- Main assays included western blotting, immunofluorescence, laser micro-irradiation, ChIP at AsiSI-induced DSBs, comet assays, an I-Sce1-based HR assay, random-plasmid integration for NHEJ, and live-cell imaging of GFP-Ku70 and GFP-Artemis.
Limitations
- The paper states that it cannot rule out that HDAC1 and HDAC2 influence DSB repair by directly targeting NHEJ factors or other regulators, such as ATM, in addition to deacetylating histones.
- The paper notes that H3K56Ac regulation may differ between organisms and genomic locations, citing contrasting findings for SIRT6 and mouse cells.
- Evident from the text: the work relies mainly on cultured human cell lines and siRNA/inhibitor approaches, and the authors state that systematic identification of HDAC1/2 substrates remains needed.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 12 cited sources checked · 0 supported · 0 flagged
- Findingown data
Activity of Class I/II HDACs is needed for H3K56Ac loss upon DNA damage induction.
“the activity of such HDACs is also needed for H3K56Ac loss upon DNA damage induction.”
Quote in the paperSubstantial claim- Rests on an assumption: The Class I/II HDAC inhibitors TSA and NaB specifically inhibit HDAC1/2 deacetylase activity.
- Findingcitation
H3K56 acetylation is negatively regulated by DNA damage in human cells.
“we recently found that H3K9 and H3K56 acetylations (H3K9Ac and H3K56Ac) are negatively regulated by DNA damage20.”
- Also stated in: § H3K56Ac levels are reduced upon DNA damage · boosted
“Taken together, these results established that H3K56Ac levels are reduced at sites of DNA damage.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Tjeertes, J.V., Miller, K.M. & Jackson, S.P. Screen for DNA-damage-responsive histone modifications identifies H3K9Ac and H3K56Ac in human cells. EMBO J. 28, 1878–1889 (2009). source
Not checked in the free run.
- Rests on an assumption: The loss of H3K56Ac signal at DNA-damage sites reflects deacetylation of H3K56 rather than histone eviction or epitope masking.
- Also stated in: § H3K56Ac levels are reduced upon DNA damage · boosted
- Findingown data
Class I/II HDACs regulate H3K56Ac levels under normal growth conditions.
“This suggested that Class I/II HDACs regulate H3K56Ac levels under normal growth conditions.”
Quote in the paperSubstantial claim- Rests on an assumption: The Class I/II HDAC inhibitors TSA and NaB specifically inhibit HDAC1/2 deacetylase activity.
- Findingown data
Depletion of HDAC3 does not yield H3K56Ac or H4K16Ac hyper-acetylation.
“depletion of HDAC3, which we had found not to be detectably recruited to DNA-damage sites, did not yield H3K56Ac or H4K16Ac hyper-acetylation”
Quote in the paperSubstantial claim- Rests on an assumption: The anti-H3K56Ac antibodies used are specific for H3K56Ac.
- Findingown data
Endogenous HDAC1 and HDAC2, but not HDAC3 or HDAC8, are recruited to sites of laser-induced DNA damage.
“we could detect the recruitment of endogenous HDAC1 and HDAC2, but not HDAC3 or HDAC8, to sites of laser micro-irradiation”
Quote in the paperSubstantial claim- Rests on an assumption: The laser micro-irradiation and AsiSI-ER systems produce DNA damage that is representative of physiological DSBs for studying HDAC1/2 recruitment and H3K56 deacetylation.
- Findingown data
H3K56Ac intensity at IR-induced foci is inversely correlated with γH2AX or 53BP1 intensity.
“H3K56Ac exhibited punctate staining, the intensity of which was inversely correlated with that of γH2AX or 53BP1”
Quote in the paperNot a substantial claim- Rests on an assumption: The anti-H3K56Ac antibodies used are specific for H3K56Ac.
- Findingown data
H4K16Ac displays a biphasic response at DNA-damage sites: reduced at early time points and enhanced at later times.
“H4K16Ac displayed a biphasic response at DNA-damage sites: being reduced at early time points, (Fig. 2e) but enhanced at later times (Fig. 2f).”
Quote in the paperNot a substantial claim - Findingown data
Late-passage human diploid fibroblasts displaying replicative senescence exhibit lower H3K56Ac levels than earlier-passage cells.
“late-passage human diploid fibroblasts displaying replicative senescence exhibited lower H3K56Ac levels than earlier-passage cells”
Quote in the paperNot a substantial claim- Rests on an assumption: The loss of H3K56Ac signal at DNA-damage sites reflects deacetylation of H3K56 rather than histone eviction or epitope masking.
- Findingown data
HDAC1/2 depletion in HeLa cells results in hyper-acetylation of H3K56Ac as detected by two different anti-H3K56Ac antibodies.
“HDAC1/2-depletion in HeLa cells also resulted in hyper-acetylation of H3K56Ac as detected by two different anti-H3K56Ac antibodies”
Quote in the paperSubstantial claim- Rests on an assumption: The anti-H3K56Ac antibodies used are specific for H3K56Ac.
- Findingown data
siRNA-mediated depletion of HDAC1 and HDAC2 together, but not either alone, causes H3K56 and H4K16 hyper-acetylation in U2OS cells.
“siRNA-mediated depletion of HDAC1 and HDAC2 together, but not of either alone, caused H3K56 and H4K16 hyper-acetylation in U2OS cells”
Quote in the paperSubstantial claim- Rests on an assumption: The anti-H3K56Ac antibodies used are specific for H3K56Ac.
- Findingown data
H3K56Ac staining is diminished at sites of DNA damage containing γH2AX.
“staining for H3K56Ac was diminished at sites of DNA damage containing γH2AX”
Quote in the paperSubstantial claim- Rests on an assumption: The loss of H3K56Ac signal at DNA-damage sites reflects deacetylation of H3K56 rather than histone eviction or epitope masking.
- Rests on an assumption: The anti-H3K56Ac antibodies used are specific for H3K56Ac.
- Findingown data
HDAC1/2 depletion or HDAC-inhibitor treatment leads to higher amounts of γH2AX produced in response to DNA damage than in control cells.
“HDAC1/2 depletion or HDAC-inhibitor treatment led to higher amounts of gH2AX being produced in response to DNA damage than in control cells”
Quote in the paperSubstantial claim- Rests on an assumption: The Class I/II HDAC inhibitors TSA and NaB specifically inhibit HDAC1/2 deacetylase activity.
- Findingown data
Artemis persistence at sites of DNA damage is greater in HDAC1/2-depleted cells than in Ligase IV-depleted cells.
“the persistence of Artemis at sites of DNA damage was greater in HDAC1/2-depleted cells than in Ligase IV-depleted cells”
Quote in the paperSubstantial claim - Findingown data
GFP-tagged Ku70 and Artemis are rapidly recruited to sites of laser-induced DNA damage.
“green-fluorescent protein (GFP)-tagged Ku70 and Artemis were rapidly recruited to sites of laser-induced DNA damage”
Quote in the paperNot a substantial claim - Findingown data
HDAC1/2 depletion produces similar increased association of Ku70 and Artemis with damaged regions.
“HDAC1/2 depletion produced similar results”
Quote in the paperSubstantial claim - Findingown data
The repair of IR- and phleomycin-induced DSBs is markedly impaired by HDAC1/2 depletion.
“the repair of IR- and phleomycin-induced DSBs was markedly impaired by HDAC1/2 depletion”
Quote in the paperSubstantial claim - Findingown data
The levels of endogenous and induced DSBs are similar in control and HDAC1/2 depleted cells.
“while the levels of endogenous and induced DSBs were similar in control and HDAC1/2 depleted cells”
Quote in the paperSubstantial claim - Findingown data
Ku70 and Artemis display increased association with damaged regions in cells treated with HDAC inhibitors compared to control cells.
“both Ku70 and Artemis displayed increased association with damaged regions in cells treated with HDAC inhibitors as compared to control cells”
Quote in the paperSubstantial claim- Rests on an assumption: The Class I/II HDAC inhibitors TSA and NaB specifically inhibit HDAC1/2 deacetylase activity.
- Findingown data
HDAC1/2-depleted cells exhibit a modest reduction in homologous recombination as measured by an I-Sce1 based HR assay.
“HDAC1/2-depleted cells exhibited defective DSB repair as revealed by a modest reduction in homologous recombination (HR) as measured by a I-Sce1 based HR assay”
Quote in the paperNot a substantial claim - Findingown data
HDAC1/2 depletion causes hypersensitivity to the DSB-inducing agents IR and phleomycin.
“HDAC1/2 depletion caused hypersensitivity to the DSB-inducing agents IR and phleomycin”
Quote in the paperSubstantial claim - Findingown data
HDAC1/2 depletion leads to higher levels of DNA-damage induced auto-phosphorylation (S2056p) and ATM-mediated phosphorylation (T2609p) of DNA-PKcs.
“HDAC1/2 depletion led to higher levels of DNA-damage induced auto-phosphorylation (S2056p) and ATM-mediated phosphorylation (T2609p) of the NHEJ factor DNA-PKcs”
Quote in the paperSubstantial claim - Findingown data
HDAC1/2 depletion does not markedly affect DDR markers arising when cells are treated with camptothecin.
“HDAC1/2 depletion did not markedly affect DDR markers arising when cells were treated with camptothecin”
Quote in the paperNot a substantial claim - Findingown data
HDAC inhibitors cause NHEJ factors Ku70/80 and XRCC4 to display enhanced associations with an AsiSI-ER induced site-specific DSB.
“HDAC inhibitors caused the NHEJ factors Ku70/80 and XRCC4 to display enhanced associations with an AsiSI-ER induced site-specific DSB”
Quote in the paperSubstantial claim- Rests on an assumption: The Class I/II HDAC inhibitors TSA and NaB specifically inhibit HDAC1/2 deacetylase activity.
- Findingown data
HDAC1/2-depleted cells exhibit a major defect in non-homologous end-joining as measured by random-plasmid integration.
“a major defect in non-homologous end-joining (NHEJ) as measured by random-plasmid integration”
Quote in the paperSubstantial claim - Findingown data
Recombinant HDAC1 deacetylates H3K56Ac and H4K16Ac on calf histones in vitro.
“recombinant HDAC1 deacetylated these sites on calf histones in vitro”
Quote in the paperSubstantial claim - Findingown data
DNA-damage induced phosphorylations of CHK1, CHK2 and p53 are higher and more sustained in HDAC1/2 depleted cells than in control cells.
“DNA-damage induced phosphorylations of CHK1, CHK2 and p53 were also higher and more sustained in HDAC1/2 depleted cells than in control cells”
Quote in the paperSubstantial claim - Interpretationown data
HDAC1/2 mediated protein deacetylations, including those on H3K56 and H4K16, promote DSB repair, particularly NHEJ.
“Our data suggest a model in which HDAC1/2 mediated protein deacetylations, including those on H3K56 and H4K16, promote DSB repair, particularly NHEJ”
Quote in the paperSubstantial claim- Rests on an assumption: The loss of H3K56Ac signal at DNA-damage sites reflects deacetylation of H3K56 rather than histone eviction or epitope masking.
- Interpretationreasoning
HDAC1 and HDAC2 promote proper DSB signalling and repair, predominantly through their requirement for effective NHEJ.
“These data therefore indicated that HDAC1 and HDAC2 promote proper DSB signalling and repair, predominately through their requirement for effective NHEJ.”
Quote in the paperSubstantial claim - Interpretationreasoning
HDAC1/2 and their targets H3K56Ac and H4K16Ac are potentially involved, through their impact on NHEJ, in modulating a cancer cell's susceptibility to HDAC inhibitors and DNA-damage based therapies.
“Our data highlight the potential for HDAC1 and HDAC2, as well as their targets, H3K56Ac and H4K16Ac, to be involved – through their impact on NHEJ – in modulating a cancer cells’ susceptibility to HDAC inhibitors and DNA-damage based therapies.”
Quote in the paperSubstantial claim - Study design and conductown data
The effects of HDAC1/2 depletion on H3K56Ac and H4K16Ac levels are circumvented by a siRNA-resistant HDAC1 derivative.
“the effects of HDAC1/2 depletion on H3K56Ac and H4K16Ac levels were circumvented when a siRNA-resistant HDAC1 derivative was employed”
Quote in the paperSubstantial claim - Study design and conductown data
Pair-wise combinations of various HDAC1- or HDAC2-targeting siRNA oligonucleotides also induced H3K56Ac and H4K16Ac.
“induction of H3K56Ac and H4K16Ac was also observed when we used pair-wise combinations of various HDAC1- or HDAC2-targeting siRNA oligonucleotides”
Quote in the paperNot a substantial claim - Study design and conductown data
HDAC1/2 depletion did not appreciably affect cell-cycle distributions.
“HDAC1/2 depletion did not appreciably affect cell-cycle distributions”
Quote in the paperNot a substantial claim - Study design and conductcitation
The observed decrease in H3K56Ac levels was not due to effects of DNA damage on cell-cycle distributions, as this histone mark is not cell cycle regulated.
“the observed decrease in H3K56Ac levels were not due to effects of DNA damage on cell-cycle distributions, as this histone mark is not cell cycle regulated20,35”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [20] Tjeertes, J.V., Miller, K.M. & Jackson, S.P. Screen for DNA-damage-responsive histone modifications identifies H3K9Ac and H3K56Ac in human cells. EMBO J. 28, 1878–1889 (2009). source
Not checked in the free run.
- cites [35] Xie, W. et al. Histone h3 lysine 56 acetylation is linked to the core transcriptional network in human embryonic stem cells. Mol. Cell 33, 417–427 (2009). source
Not checked in the free run.
- Interpretationown data
HDAC1 and HDAC2 promote NHEJ, at least in part by regulating the proper assembly and/or disassembly of NHEJ factors from DSB sites.
“Together, these results thereby established that HDAC1 and HDAC2 promote NHEJ, at least in part by regulating the proper assembly and/or disassembly of NHEJ factors from DSB sites.”
Quote in the paperSubstantial claim
- May combine two claims. 11
- Classified as probably not a substantial claim. 4
May combine two claims.
Findingown dataH4K16Ac is reduced by replicative senescence but enhanced upon oncogene-induced senescence.
“H4K16Ac was reduced by replicative senescence but enhanced upon OIS”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataHDAC1/2 accumulation at DNA damage sites occurs within 5 minutes and declines, no longer visible after 30 minutes.
“HDAC1/2 accumulation occurred within 5 minutes of DNA-damage induction and then gradually declined, being no longer visible after 30 minutes”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAsiSI-ER induction decreases H3K56Ac at DSB sites but not at a site without an AsiSI sequence.
“AsiSI-ER induction decreased H3K56Ac at DSB sites, while no reduction was observed at another site that did not contain an AsiSI sequence”
Quote in the paperSubstantial claim- Rests on an assumption: The loss of H3K56Ac signal at DNA-damage sites reflects deacetylation of H3K56 rather than histone eviction or epitope masking.
- Rests on an assumption: The laser micro-irradiation and AsiSI-ER systems produce DNA damage that is representative of physiological DSBs for studying HDAC1/2 recruitment and H3K56 deacetylation.
May combine two claims.
Findingown dataClass I/II HDAC inhibitors suppress H3K56 deacetylation at laser micro-irradiation sites and block localization of HDAC1 and HDAC2 to DNA-damage regions.
“Class I/II HDAC inhibitors suppressed H3K56 deacetylation at sites of laser micro-irradiation and also blocked the localization of HDAC1 and HDAC2 to DNA-damage regions”
Quote in the paperSubstantial claim- Rests on an assumption: The Class I/II HDAC inhibitors TSA and NaB specifically inhibit HDAC1/2 deacetylase activity.
May combine two claims.
Findingown dataHuman diploid fibroblasts exhibiting oncogene-induced senescence due to RAS over-expression display decreased H3K56Ac and H3K56Ac exclusion from DNA-damage sites.
“human diploid fibroblast exhibiting OIS due to RAS over-expression32-34 displayed decreased H3K56Ac compared to control cells, as well as H3K56Ac exclusion from DNA-damage sites”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [32] Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006). source
Not checked in the free run.
- cites [33] Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006). source
Not checked in the free run.
- cites [34] Serrano, M., Lin, A.W., McCurrach, M.E., Beach, D. & Lowe, S.W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997). source
Not checked in the free run.
- Rests on an assumption: The loss of H3K56Ac signal at DNA-damage sites reflects deacetylation of H3K56 rather than histone eviction or epitope masking.
May combine two claims.
Findingown dataSirtuin inhibitor nicotinamide or depletion of SIRT1 and SIRT2 causes little or no increase in H3K56Ac or H4K16Ac.
“when we treated cells with the Sirtuin inhibitor nicotinamide or depleted cells of SIRT1 and SIRT2, little or no increase in H3K56Ac or H4K16Ac was observed”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationBroad specificity HDAC inhibitors sensitize cancer cells to DNA-damaging treatments.
“broad specificity HDAC inhibitors are promising anti-cancer drugs that sensitize cancer cells to DNA-damaging treatments24,27,28”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [24] Glozak, M.A. & Seto, E. Histone deacetylases and cancer. Oncogene 26, 5420–5432 (2007). source
Not checked in the free run.
- cites [27] Smith, K.T. & Workman, J.L. Histone deacetylase inhibitors: anticancer compounds. Int. J. Biochem. Cell Biol. 41, 21–25 (2009). source
Not checked in the free run.
- cites [28] Camphausen, K. & Tofilon, P.J. Inhibition of histone deacetylation: a strategy for tumor radiosensitization. J. Clin. Oncol. 25, 4051–4056 (2007). source
Not checked in the free run.
May combine two claims.
Study design and conductown dataThe effects on H3K56Ac are specific because H3K14Ac did not decrease at either DSB site, while γH2AX was increased.
“the effects on H3K56Ac are specific because H3K14Ac did not decrease at either DSB site, while γH2AX was increased”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataHDAC1/2 depletion does not affect the amount of DNA damage produced by DSB-inducing agents but impairs DNA repair.
“Collectively, the above data suggested that HDAC1/2 depletion or inhibition does not affect the amount of DNA damage produced by DSB-inducing agents but, rather, impairs DNA repair.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataAnalysis of p53 acetylation revealed that nicotinamide was effective in the assays.
“analysis of p53 acetylation, a known Sirtuin target40,41, revealed that nicotinamide was effective in our assays”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [40] Luo, J. et al. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 107, 137–148 (2001). source
Not checked in the free run.
- cites [41] Cheng, H.L. et al. Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc. Natl. Acad. Sci. USA 100, 10794–10799 (2003). source
Not checked in the free run.
May combine two claims.
Study design and conductown dataHDAC1/2-depleted cells expressed normal levels of core NHEJ factors, ruling out indirect transcriptional effects.
“HDAC1/2-depleted cells expressed normal levels of core NHEJ factors, thus ruling out indirect transcriptional effects”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataAntibody specificities for HDAC1 and HDAC2 were verified.
“antibody specificities for HDAC1 and HDAC2 are verified in Supplementary Fig. 1”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe enhanced accrual of Ku and Artemis at sites of DNA damage upon HDAC1/2 inactivation is not only due to impaired NHEJ but also reflects the NHEJ machinery unproductively spreading onto chromatin flanking the DSB sites.
“the enhanced accrual of Ku and Artemis at sites of DNA damage that we observe upon HDAC1/2 inactivation is not only due to impaired NHEJ but also reflects the NHEJ machinery unproductively spreading onto chromatin flanking the DSB sites.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHDAC1/2 are overexpressed in many cancers.
“HDAC1/2 are overexpressed in many cancers24”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [24] Glozak, M.A. & Seto, E. Histone deacetylases and cancer. Oncogene 26, 5420–5432 (2007). source
Not checked in the free run.
May combine two claims.
InterpretationreasoningHistone acetylation changes following DSB induction occur in a biphasic manner, with rapid deacetylation at sites such as H3K56 and H4K16 promoting NHEJ, followed by histone acetylations that enhance HR.
“we suggest that histone acetylation changes are likely to occur in a biphasic manner following DSB induction, with rapid deacetylation on sites such as H3K56 and H4K16 occurring to promote NHEJ (possibly by generating a less dynamic “repressed” chromatin state) being followed by histone acetylations that enhance HR”
Quote in the paperSubstantial claim- Rests on an assumption: The loss of H3K56Ac signal at DNA-damage sites reflects deacetylation of H3K56 rather than histone eviction or epitope masking.
The paper relies on this without support.
The loss of H3K56Ac signal at DNA-damage sites reflects deacetylation of H3K56 rather than histone eviction or epitope masking.
“staining for H3K56Ac was diminished at sites of DNA damage containing γH2AX”
“AsiSI-ER induction decreased H3K56Ac at DSB sites”
The paper relies on this without support.
The laser micro-irradiation and AsiSI-ER systems produce DNA damage that is representative of physiological DSBs for studying HDAC1/2 recruitment and H3K56 deacetylation.
“we could detect the recruitment of endogenous HDAC1 and HDAC2, but not HDAC3 or HDAC8, to sites of laser micro-irradiation”
“AsiSI-ER induction decreased H3K56Ac at DSB sites”
The paper relies on this without support.
The anti-H3K56Ac antibodies used are specific for H3K56Ac.
“as detected by two different anti-H3K56Ac antibodies”
“staining for H3K56Ac was diminished at sites of DNA damage containing γH2AX”
The paper relies on this without support.
The Class I/II HDAC inhibitors TSA and NaB specifically inhibit HDAC1/2 deacetylase activity.
“TSA and NaB but not nicotinamide, resulted in increased H3K56Ac levels”
“Class I/II HDAC inhibitors suppressed H3K56 deacetylation at sites of laser micro-irradiation”
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?
HDAC1/2 deacetylate H3K56 to promote NHEJ repair.
“By deacetylating of H3K56, they promote NHEJ repair (Miller et al., 2010).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Miller et al., 2010
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
TSA and NaB are assigned to conflicting HDAC inhibitor classes
MinorThe paper first identifies TSA and NaB as Class I/II HDAC inhibitors, but later calls the same two compounds Class I/III HDAC inhibitors.
“the Class I/II HDAC inhibitors Trichostatin A (TSA) and sodium butyrate (NaB), or by the Sirtuin inhibitor, nicotinamide.”
“treating cells with the Class I/III HDAC inhibitors TSA or NaB enhanced both H3K56Ac and H4K16Ac”
Cites
Chromatin modifications and their function
Kouzarides, T. (2007) · Cell · doi:10.1016/j.cell.2007.02.005 · Cited by 10,883 · see citing works
The DNA-damage response in human biology and disease
Jackson, S. P., & Bartek, J. (2009) · Nature · doi:10.1038/nature08467 · Cited by 6,092 · see citing works
Self-citationOncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,178 · cited 1× · see citing works
“Human diploid fibroblasts showing OIS as a result of RAS overexpressio”
The Role of Chromatin during Transcription
Li, B., Carey, M., & Workman, J. L. (2007) · Cell · doi:10.1016/j.cell.2007.01.015 · Cited by 3,503 · see citing works
A DNA damage checkpoint response in telomere-initiated senescence
Fagagna, F. D. D., Reaper, P. M., Clay-Farrace, L., Fiegler, H., Carr, P., von Zglinicki, T., Saretzki, G., Carter, N. P., & Jackson, S. P. (2003) · Nature · doi:10.1038/nature02118 · Cited by 2,855 · see citing works
Self-citationDNA damage response as a candidate anti-cancer barrier in early human tumorigenesis
Bartkova, J., Hořejší, Z., Koed, K., Krämer, A., Tort, F., Zieger, K., Guldberg, P., Sehested, M., Nesland, J. M., Lukas, C., et al. (2005) · Nature · doi:10.1038/nature03482 · Cited by 2,688 · see citing works
Mammalian Sirtuins: Biological Insights and Disease Relevance
Haigis, M. C., & Sinclair, D. A. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev.pathol.4.110807.092250 · Cited by 2,085 · see citing works
Negative Control of p53 by Sir2α Promotes Cell Survival under Stress
Luo, J., Nikolaev, A. Y., Imai, S.-I., Chen, D., Su, F., Shiloh, A., Guarente, L., & Gu, W. (2001) · Cell · doi:10.1016/s0092-8674(01)00524-4 · Cited by 2,081 · see citing works
Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions
Gorgoulis, V. G., Vassiliou, L.-V. F., Karakaidos, P., Zacharatos, P., Kotsinas, A., Liloglou, T., Venere, M., DiTullio, R. A., Kastrinakis, N. G., Levy, B., et al. (2005) · Nature · doi:10.1038/nature03485 · Cited by 2,009 · see citing works
Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints
Bartkova, J., Rezaei, N., Liontos, M., Karakaidos, P., Kletsas, D., Issaeva, N., Vassiliou, L.-V. F., Kolettas, E., Niforou, K., Zoumpourlis, V. C., et al. (2006) · Nature · doi:10.1038/nature05268 · Cited by 1,986 · see citing works
Fraga, M. F., Ballestar, E., Villar‐Garea, A., Boix-Chornet, M., Espada, J., Schotta, G., Bonaldi, T., Haydon, C. E., Ropero, S., Petrie, K. R., et al. (2005) · Nature Genetics · doi:10.1038/ng1531 · Cited by 1,926 · see citing works
Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication
Di Micco, R., Fumagalli, M., Cicalese, A., Piccinin, S., Gasparini, P., Luise, C., Schurra, C., Garre’, M., Giovanni Nuciforo, P., Bensimon, A., et al. (2006) · Nature · doi:10.1038/nature05327 · Cited by 1,821 · see citing works
The DNA Damage Response: Ten Years After
Harper, J. W., & Elledge, S. J. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.11.015 · Cited by 1,705 · see citing works
Bonner, W. M., Redon, C. E., Dickey, J. S., Nakamura, A. J., Sedelnikova, O. A., Solier, S., & Pommier, Y. (2008) · Nature reviews. Cancer · doi:10.1038/nrc2523 · Cited by 1,623 · see citing works
Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes
Wang, Z., Zang, C., Cui, K., Schones, D. E., Barski, A., Peng, W., & Zhao, K. (2009) · Cell · doi:10.1016/j.cell.2009.06.049 · Cited by 1,344 · see citing works
The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men
Yang, X., & Seto, E. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2346 · Cited by 1,239 · see citing works
The DNA-dependent protein kinase: Requirement for DNA ends and association with Ku antigen
Gottlieb, T. M., & Jackson, S. P. (1993) · Cell · doi:10.1016/0092-8674(93)90057-w · Cited by 1,233 · see citing works
Self-citationLiving on a break: cellular senescence as a DNA-damage response
d'Adda di Fagagna, F. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2440 · Cited by 1,170 · see citing works
RNF8 Ubiquitylates Histones at DNA Double-Strand Breaks and Promotes Assembly of Repair Proteins
Mailand, N., Bekker‐Jensen, S., Kildegaard, H. F., Melander, F., Bártek, J., Lukas, C., & Lukas, J. (2007) · Cell · doi:10.1016/j.cell.2007.09.040 · Cited by 1,153 · see citing works
Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice
Cheng, H.-L., Mostoslavsky, R., Saito, S., Manis, J. P., Gu, Y., Patel, P., Bronson, R., Appella, E., Alt, F. W., & Chua, K. F. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1934713100 · Cited by 1,095 · see citing works
Histone deacetylases and cancer
Glozak, M. A., & Seto, E. (2007) · Oncogene · doi:10.1038/sj.onc.1210610 · Cited by 1,031 · see citing works
RNF8 Transduces the DNA-Damage Signal via Histone Ubiquitylation and Checkpoint Protein Assembly
Huen, M. S. Y., Grant, R. A., Manke, I. A., Minn, K. T., Yu, X., Yaffe, M. B., & Chen, J. (2007) · Cell · doi:10.1016/j.cell.2007.09.041 · Cited by 1,027 · see citing works
Doil, C., Mailand, N., Bekker‐Jensen, S., Ménard, P., Larsen, D. H., Pepperkok, R., Ellenberg, J., Panier, S., Durocher, D., Bártek, J., et al. (2009) · Cell · doi:10.1016/j.cell.2008.12.041 · Cited by 938 · see citing works
Orchestration of the DNA-Damage Response by the RNF8 Ubiquitin Ligase
Kolas, N. K., Chapman, J. R., Nakada, S., Ylanko, J., Chahwan, R., Sweeney, F. D., Panier, S., Mendez, M., Wildenhain, J., Thomson, T. M., et al. (2007) · Science · doi:10.1126/science.1150034 · Cited by 900 · see citing works
Self-citationATM Signaling Facilitates Repair of DNA Double-Strand Breaks Associated with Heterochromatin
Goodarzi, A. A., Noon, A. T., Deckbar, D., Ziv, Y., Shiloh, Y., Löbrich, M., & Jeggo, P. A. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.05.017 · Cited by 836 · see citing works
The RIDDLE Syndrome Protein Mediates a Ubiquitin-Dependent Signaling Cascade at Sites of DNA Damage
Stewart, G. S., Panier, S., Townsend, K., Al-Hakim, A., Kolas, N. K., Miller, E. S., Nakada, S., Ylanko, J., Olivarius, S., Mendez, M., et al. (2009) · Cell · doi:10.1016/j.cell.2008.12.042 · Cited by 757 · see citing works
Chromatin Challenges during DNA Replication and Repair
Groth, A., Rocha, W., Verreault, A., & Almouzni, G. (2007) · Cell · doi:10.1016/j.cell.2007.01.030 · Cited by 733 · see citing works
Repair of ionizing radiation-induced DNA double-strand breaks by non-homologous end-joining
Mahaney, B. L., Meek, K., & Lees‐Miller, S. P. (2009) · Biochemical Journal · doi:10.1042/bj20080413 · Cited by 722 · see citing works
CBP/p300-mediated acetylation of histone H3 on lysine 56
Das, C., Lucia, M. S., Hansen, K. C., & Tyler, J. K. (2009) · Nature · doi:10.1038/nature07861 · Cited by 698 · see citing works
Murr, R., Loizou, J. I., Yang, Y.-G., Cuenin, C., Li, H., Wang, Z.-Q., & Herceg, Z. (2006) · Nature Cell Biology · doi:10.1038/ncb1343 · Cited by 613 · cited 1× · see citing works
“Histone acetylations, together with the enzymes that mediate their addition and removal, have also been implicated in the DDR, although their modes of action are less well defined than those of histone phosphorylations and ubiquitylation”
Acetylation of histone H4 by Esa1 is required for DNA double-strand break repair
Bird, A. W., Yu, D. Y., Pray-Grant, M. G., Qiu, Q., Harmon, K. E., Megee, P. C., Grant, P. A., Smith, M. M., & Christman, M. F. (2002) · Nature · doi:10.1038/nature01035 · Cited by 565 · see citing works
Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks
Galanty, Y., Belotserkovskaya, R., Coates, J., Polo, S. E., Miller, K. M., & Jackson, S. P. (2009) · Nature · doi:10.1038/nature08657 · Cited by 520 · see citing works
Self-citationHigh‐resolution profiling of γH2AX around DNA double strand breaks in the mammalian genome
Iacovoni, J. S., Caron, P., Lassadi, I., Nicolas, E., Massip, L., Trouche, D., & Legube, G. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.38 · Cited by 515 · see citing works
Self-citationThe emerging role of nuclear architecture in DNA repair and genome maintenance
Misteli, T., & Soutoglou, E. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2651 · Cited by 468 · see citing works
Dynamic assembly of end-joining complexes requires interaction between Ku70/80 and XRCC4
Mari, P., Florea, B. I., Persengiev, S. P., Verkaik, N. S., Brüggenwirth, H. T., Modesti, M., Giglia‐Mari, G., Bezstarosti, K., Demmers, J., Luider, T. M., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0609061103 · Cited by 423 · see citing works
Autophosphorylation of DNA-PKCS regulates its dynamics at DNA double-strand breaks
Uematsu, N., Weterings, E., Yano, K., Morotomi‐Yano, K., Jakob, B., Taucher-Scholz, G., Mari, P., van Gent, D. C., Chen, B. P. C., & Chen, D. J. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200608077 · Cited by 414 · see citing works
γH2AX and MDC1: Anchoring the DNA-damage-response machinery to broken chromosomes
Stucki, M., & Jackson, S. P. (2006) · DNA Repair · doi:10.1016/j.dnarep.2006.01.012 · Cited by 412 · see citing works
Self-citationDNA resection in eukaryotes: deciding how to fix the break
Huertas, P. (2010) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1710 · Cited by 398 · see citing works
Cell cycle-dependent deacetylation of telomeric histone H3 lysine K56 by human SIRT6
Michishita, E., McCord, R. A., Boxer, L. D., Barber, M. F., Hong, T., Gozani, O., & Chua, K. F. (2009) · Cell Cycle · doi:10.4161/cc.8.16.9367 · Cited by 384 · see citing works
Screen for DNA‐damage‐responsive histone modifications identifies H3K9Ac and H3K56Ac in human cells
Tjeertes, J. V., Miller, K. M., & Jackson, S. P. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.119 · Cited by 347 · see citing works
Self-citationRepair of and checkpoint response to topoisomerase I-mediated DNA damage
Pommier, Y. G., Redon, C., Rao, V. A., Seiler, J. A., Sordet, O., Takemura, H., Antony, S., Meng, L., Liao, Z., Kohlhagen, G., et al. (2003) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2003.08.016 · Cited by 299 · see citing works
Histone deacetylase 1 (HDAC1), but not HDAC2, controls embryonic stem cell differentiation
Dovey, O. M., Foster, C. T., & Cowley, S. M. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1000478107 · Cited by 298 · see citing works
Chromatin dynamics and the preservation of genetic information
Downs, J. A., Nussenzweig, M. C., & Nussenzweig, A. (2007) · Nature · doi:10.1038/nature05980 · Cited by 285 · see citing works
The sirtuin SIRT6 deacetylates H3 K56Ac in vivo to promote genomic stability
Yang, B., Zwaans, B. M. M., Eckersdorff, M., & Lombard, D. B. (2009) · Cell Cycle · doi:10.4161/cc.8.16.9329 · Cited by 254 · see citing works
Histone deacetylase inhibitors: Signalling towards p21cip1/waf1
Ocker, M., & Schneider‐Stock, R. (2007) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2007.03.001 · Cited by 252 · see citing works
Histone H3-K56 acetylation is important for genomic stability in mammals
Yuan, J., Pu, M., Zhang, Z., & Lou, Z. (2009) · Cell Cycle · doi:10.4161/cc.8.11.8620 · Cited by 247 · see citing works
Xie, W., Song, C., Young, N. L., Sperling, A. S., Xu, F., Sridharan, R., Conway, A. E., Garcia, B. A., Plath, K., Clark, A. T., et al. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.02.004 · Cited by 197 · see citing works
Inhibition of Histone Deacetylation: A Strategy for Tumor Radiosensitization
Camphausen, K., & Tofilon, P. J. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2007.11.6202 · Cited by 162 · see citing works
(2002) · PubMed · Cited by 156 · see citing works
Saccharomyces cerevisiae Sin3p facilitates DNA double-strand break repair
Jazayeri, A. R., McAinsh, A. D., & Jackson, S. P. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0304797101 · Cited by 144 · see citing works
Self-citationSensing of Ionizing Radiation-induced DNA Damage by ATM through Interaction with Histone Deacetylase
Kim, G. D., Choi, Y. H., Dimtchev, A., Jeong, S. J., Dritschilo, A., & Jung, M. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.44.31127 · Cited by 109 · see citing works
What histone code for DNA repair?
Escargueil, A. E., Soares, D. G., Salvador, M. M., Larsen, A. K., & Henriques, J. A. P. (2008) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2008.01.004 · Cited by 97 · see citing works
Histone deacetylase inhibitors: Anticancer compounds
Smith, K. T., & Workman, J. L. (2009) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2008.09.008 · Cited by 90 · see citing works
Role of HDAC1 in senescence, aging, and cancer
Willis-Martinez, D., Richards, H. W., Timchenko, N. A., & Medrano, E. E. (2009) · Experimental Gerontology · doi:10.1016/j.exger.2009.10.001 · Cited by 85 · see citing works
Regulation of Histone H3 Lysine 56 Acetylation in Schizosaccharomyces pombe
Xhemalçe, B., Miller, K. M., Driscoll, R., Masumoto, H., Jackson, S. P., Kouzarides, T., Verreault, A., & Arcangioli, B. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m701197200 · Cited by 75 · see citing works
Self-citationLoading of the Nonhomologous End Joining Factor, Ku, on Protein-occluded DNA Ends
Roberts, S. A., & Ramsden, D. A. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m611125200 · Cited by 50 · see citing works
Higashiura, M., Shimizu, Y., Tanimoto, M., et al. (1992) · Experimental Cell Research · doi:10.1016/0014-4827(92)90293-h · Cited by 50 · see citing works
Rimkus, S. A., Katzenberger, R. J., Trinh, A. T., Dodson, G. E., Tibbetts, R. S., & Wassarman, D. A. (2008) · Genes & Development · doi:10.1101/gad.1639608 · Cited by 42 · see citing works
Taking It Off: Regulation of H3 K56 Acetylation by Hst3 and Hst4
Miller, K. M., Maas, N. L., & Toczyski, D. P. (2006) · Cell Cycle · doi:10.4161/cc.5.22.3501 · Cited by 33 · see citing works
Self-citationA histone code for the DNA damage response in mammalian cells?
Corpet, A., & Almouzni, G. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.180 · Cited by 26 · see citing works
Activation of a unique p53-dependent DNA damage response
Yang, J., Ahmed, A., & Ashcroft, M. A. (2009) · Cell Cycle · doi:10.4161/cc.8.10.8326 · Cited by 15 · see citing works
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Mateo, J., Carreira, S., Sandhu, S., Miranda, S., Mossop, H., Perez-Lopez, R., Nava Rodrigues, D., Robinson, D., Omlin, A., Tunariu, N., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1506859 · Cited by 2,185 · see citing works
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Polo, S. E., & Jackson, S. P. (2011) · Genes & Development · doi:10.1101/gad.2021311 · Cited by 1,092 · see citing works
Self-citationSmall-molecule–induced DNA damage identifies alternative DNA structures in human genes
Rodriguez, R., Miller, K. M., Forment, J. V., Bradshaw, C. R., Nikan, M., Britton, S., Oelschlaegel, T., Xhemalce, B., Balasubramanian, S., & Jackson, S. P. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.780 · Cited by 741 · see citing works
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Aymard, F., Bugler, B., Schmidt, C. K., Guillou, E., Caron, P., Briois, S., Iacovoni, J. S., Daburon, V., Miller, K. M., Jackson, S. P., et al. (2014) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2796 · Cited by 668 · see citing works
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Lukas, J., Lukas, C., & Bartek, J. (2011) · Nature Cell Biology · doi:10.1038/ncb2344 · Cited by 645 · see citing works
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Tang, J., Cho, N. W., Cui, G., Manion, E. M., Shanbhag, N. M., Botuyan, M. V., Mer, G., & Greenberg, R. A. (2013) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2499 · Cited by 521 · see citing works
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Ayrapetov, M. K., Gursoy-Yuzugullu, O., Xu, C., Xu, Y., & Price, B. D. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1403565111 · Cited by 391 · see citing works
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Gong, F., Chiu, L.-Y., Cox, B., Aymard, F., Clouaire, T., Leung, J. W., Cammarata, M., Perez, M., Agarwal, P., Brodbelt, J. S., et al. (2015) · Genes & Development · doi:10.1101/gad.252189.114 · Cited by 247 · see citing works
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Pao, P.-C., Patnaik, D., Watson, L. A., Gao, F., Pan, L., Wang, J., Adaikkan, C., Penney, J., Cam, H. P., Huang, W.-C., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16361-y · Cited by 216 · see citing works
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Whitehead, L., Dobler, M. R., Radetich, B., Zhu, Y., Atadja, P. W., Claiborne, T., Grob, J. E., McRiner, A., Pancost, M. R., Patnaik, A., et al. (2011) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2011.06.030 · Cited by 164 · see citing works
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Xia, C., Tao, Y., Li, M., Che, T., & Qu, J. (2020) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2020.9073 · Cited by 136 · see citing works
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Maertens, O., Kuzmickas, R., Manchester, H. E., Emerson, C. E., Gavin, A. G., Guild, C. J., Wong, T. C., De Raedt, T., Bowman-Colin, C., Hatchi, E., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0879 · Cited by 95 · see citing works
Cohen, I., Rider, P., Vornov, E., Tomas, M., Tudor, C., Wegner, M., Brondani, L., Freudenberg, M., Mittler, G., Ferrando-May, E., et al. (2015) · Scientific Reports · doi:10.1038/srep14756 · Cited by 98 · see citing works
Zhou, H., Cai, Y., Liu, D., Li, M., Sha, Y., Zhang, W., Wang, K., Gong, J., Tang, N., Huang, A., et al. (2018) · Cell Proliferation · doi:10.1111/cpr.12447 · Cited by 85 · see citing works
Long, J., Fang, W. Y., Chang, L., Gao, W. H., Shen, Y., Jia, M. Y., Zhang, Y. X., Wang, Y., Dou, H. B., Zhang, W. J., et al. (2017) · Leukemia · doi:10.1038/leu.2017.130 · Cited by 78 · see citing works
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Yang, Y., Yang, C., Li, T., Yu, S., Gan, T., Hu, J., Cui, J., & Zheng, X. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-2149 · Cited by 57 · see citing works
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Jiang, Z., He, Q., Wezeman, J., Darvas, M., & Ladiges, W. (2024) · GeroScience · doi:10.1007/s11357-024-01198-w · Cited by 10 · see citing works
- Authors
- Miller, K. M., Tjeertes, J. V., Coates, J., Legube, G., Polo, S. E., Britton, S., & Jackson, S. P.
- Affiliations
- University of Cambridge (GB)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Jackson, Stephen P
- ORCID
- Venue
- Nature Structural & Molecular Biology
- Published
- 2010-08-29
- Volume
- 17
- Issue
- 9
- Pages
- 1144-1151
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC3018776
- OpenAlex
- W2008650297
- Cited by
- 629
- References
- 61
- Citations by year
- 2026: 19 · 2025: 30 · 2024: 30 · 2023: 28 · 2022: 49 · 2021: 52 · 2020: 43 · 2019: 29 · 2018: 29 · 2017: 39 · 2016: 50 · 2015: 36 · 2014: 45 · 2013: 56 · 2012: 46
- FWCI
- 19.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Funders
- Wellcome Trust (086861/Z/08/Z, 086861)
- Cancer Research UK (11224, A5290)
- Biotechnology and Biological Sciences Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- HDAC1, HDAC2, histone deacetylase, DNA damage response, DNA double-strand break repair, non-homologous end joining, H3K56 acetylation, histone hypoacetylation, chromatin modification, DNA damage signaling, radiosensitization, histone deacetylase inhibitors, cancer therapy
- MeSH terms
- DNA Repair, Histones, Humans, RNA, Small Interfering, Cell Line, Tumor, DNA Breaks, Double-Stranded, Histone Deacetylase 1, Histone Deacetylase 2
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 2026-10-08.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.
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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