Cited by 211Genomics and Chromatin DynamicsEpigenetics and DNA MethylationCancer-related gene regulation

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DOT1L and H3K79 Methylation in Transcription and Genomic Stability

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Wood, Katherine, Tellier, Michael, Murphy, Shona·2018·Biomolecules

DOI 10.3390/biom8010011PMC PMC5871980

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Abstract

The organization of eukaryotic genomes into chromatin provides challenges for the cell to accomplish basic cellular functions, such as transcription, DNA replication and repair of DNA damage. Accordingly, a range of proteins modify and/or read chromatin states to regulate access to chromosomal DNA. Yeast Dot1 and the mammalian homologue DOT1L are methyltransferases that can add up to three methyl groups to histone H3 lysine 79 (H3K79). H3K79 methylation is implicated in several processes, including transcription elongation by RNA polymerase II, the DNA damage response and cell cycle checkpoint activation. DOT1L is also an important drug target for treatment of mixed lineage leukemia (MLL)-rearranged leukemia where aberrant transcriptional activation is promoted by DOT1L mislocalisation. This review summarizes what is currently known about the role of Dot1/DOT1L and H3K79 methylation in transcription and genomic stability.

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Influential
Chemically ubiquitylated histone H2B stimulates hDot1L-mediated intranucleosomal methylation
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Method
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Background
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Background
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Background
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Background
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Influential
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Background
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BackgroundInfluential
Tails of RNA polymerase II
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Background
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Linking H3K79 trimethylation to Wnt signaling through a novel Dot1-containing complex (DotCom)Preprint
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BackgroundInfluential
The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling
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“Complex Protein Components Reference AEP AFF1/4, ENL, P-TEFb [60] AF4-associated AFF1, AF9, DOT1L, ENL, MLLT10, P-TEFb [61] AF9-associated AF9, DOT1L (mutually exclusive with AF4/AFF4, AF9, P-TEFb) [62] DotCom AF9, CTNNB1, DOT1L, ENL, MLLT6, MLLT10, SKP1, TRRAP [63] EAP AFF1/3/4, BCOR, CBX8, DOT1L, ENL, P-TEFb, RING1…”
BackgroundInfluential
Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development
Qi, H. H., Sarkissian, M., Hu, G., Wang, Z., Bhattacharjee, A., Gordon, D. B., Gonzales, M., Lan, F., Ongusaha, P. P., Huarte, M., et al. (2010) · Nature · doi:10.1038/nature09261 · Cited by 305
Role of Dot1-Dependent Histone H3 Methylation in G1 and S Phase DNA Damage Checkpoint Functions of Rad9
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Background
Disruptor of Telomeric Silencing-1 Is a Chromatin-specific Histone H3 Methyltransferase
Lacoste, N., Utley, R. T., Hunter, J. M., Poirier, G. G., & Côté, J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.c200366200 · Cited by 298
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Background
Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors
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Background
Rate of elongation by RNA polymerase II is associated with specific gene features and epigenetic modifications
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Background
Histone modifications defining active genes persist after transcriptional and mitotic inactivation
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Background
Histone H2B Ubiquitylation Controls Processive Methylation but Not Monomethylation by Dot1 and Set1
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Background
The effect of H3K79 dimethylation and H4K20 trimethylation on nucleosome and chromatin structure
Lu, X., Simon, M. D., Chodaparambil, J. V., Hansen, J. C., Shokat, K. M., & Luger, K. (2008) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1489 · Cited by 238 · cited 2×
“Crystallographic structures of recombinant nucleosomes with either unmethylated H3K79 or an H3K79me2 mimic have demonstrated that there are no significant differe ces in global nucleosomal architecture and only minor local conformational changes [69].”
Background
DOT1L inhibits SIRT1-mediated epigenetic silencing to maintain leukemic gene expression in MLL-rearranged leukemia
Chen, C.-W. D., Koche, R. P., Sinha, A. U., Deshpande, A. J., Zhu, N., Eng, R., Doench, J. G., Xu, H., Chu, S. H., Qi, J., et al. (2015) · Nature Medicine · doi:10.1038/nm.3832 · Cited by 235 · cited 3×
“While the precise mechanism by which DOT1L contributes to the gene activation process requires further investigation, a recent study showed that DOT1L inhibits the recruitment of a repressive complex composed of SIRT1 and SUV39H1, a H3K9 methyltransferase, on MLL fusion target genes, thus mai taining an open chromatin…”
Background
The pol II CTD: new twists in the tail
Zaborowska, J., Egloff, S., & Murphy, S. (2016) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3285 · Cited by 235 · cited 2×
“The CTD is subject to numerous reversible post-translational modifications on specific residues in both consensus and non-consensus repeats [51].”
BackgroundSelf-citation
Epigenetics: molecular mechanisms and implications for disease
Handel, A. E., Ebers, G. C., & Ramagopalan, S. V. (2009) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2009.11.003 · Cited by 227 · cited 1×
“Misregulation of histone lysine methylation is associated with several human cancers and other diseases [8,9].”
Background
DOT1L cooperates with the c-Myc–p300 complex to epigenetically derepress CDH1 transcription factors in breast cancer progression
Cho, M.-H., Park, J.-H., Choi, H.-J., Park, M.-K., Won, H.-Y., Park, Y.-J., Lee, C. H., Oh, S.-H., Song, Y.-S., Kim, H. S., et al. (2015) · Nature Communications · doi:10.1038/ncomms8821 · Cited by 211 · cited 1×
“C-Myc is essential for the presence of DOT1L and H3K79me2 at several genomic loci, suggesting that c-Myc targets the enzyme to these loci [54].”
Background
Misguided Transcriptional Elongation Causes Mixed Lineage Leukemia
Mueller, D., García-Cuéllar, M.-P., Bach, C., Buhl, S., Maethner, E., & Slany, R. K. (2009) · PLoS Biology · doi:10.1371/journal.pbio.1000249 · Cited by 203 · cited 4×
“Complex Protein Components Reference AEP AFF1/4, ENL, P-TEFb [60] AF4-associated AFF1, AF9, DOT1L, ENL, MLLT10, P-TEFb [61] AF9-associated AF9, DOT1L (mutually exclusive with AF4/AFF4, AF9, P-TEFb) [62] DotCom AF9, CTNNB1, DOT1L, ENL, MLLT6, MLLT10, SKP1, TRRAP [63] EAP AFF1/3/4, BCOR, CBX8, DOT1L, ENL, P-TEFb, RING1…”
Influential
Histone methyltransferase Dot1 and Rad9 inhibit single‐stranded DNA accumulation at DSBs and uncapped telomeres
Lazzaro, F., Sapountzi, V., Granata, M., Pellicioli, A., Vaze, M. B., Haber, J. E., Plevani, P., Lydall, D. A., & Muzi-Falconi, M. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.81 · Cited by 198 · cited 2×
“Dot1-dependent H3K79me is crucial in the repair of these UV-induced DNA lesions [84], as the loss of these histone marks results in UV hypersensitivity [89,91].”
Background
Interplay of Chromatin Modifiers on a Short Basic Patch of Histone H4 Tail Defines the Boundary of Telomeric Heterochromatin
Altaf, M., Utley, R. T., Lacoste, N., Tan, S., Briggs, S. D., & Côté, J. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.12.002 · Cited by 192 · cited 4×
“Alternatively, H3K79 methylation may inhibit the binding of repressors [74,75].”
BackgroundInfluential
Structure and function of the nucleosome-binding PWWP domain
Su, Q., & Min, J. (2014) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2014.09.001 · Cited by 190 · cited 6×
“The PWWP (named after a conserved ProTrp-Trp-Pro motif) domain of hepatoma-derived growth factor 2 (HDGF2) binds H3K79me3 [70], while the Tudor domain of survival of motor neuron protein (SMN) [71] and the tandem Tudor domains of 53BP1 and fragile X mental retardation protein (FMRP) also bind H3K79me [72,73].”
BackgroundInfluential
Leukemogenic MLL Fusion Proteins Bind across a Broad Region of the Hox a9 Locus, Promoting Transcription and Multiple Histone Modifications
Milne, T. A., Martin, M. E., Brock, H. W., Slany, R. K., & Hess, J. L. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-1041 · Cited by 186 · cited 1×
“However, there is considerable evidence suggesting that H3K79 methylation is reversible [36].”
Background
Linking Cell Cycle to Histone Modifications: SBF and H2B Monoubiquitination Machinery and Cell-Cycle Regulation of H3K79 Dimethylation
Schulze-Hentrich, J. M., Jackson, J., Nakanishi, S., Gardner, J. M., Hentrich, T., Haug, J., Johnston, M., Jaspersen, S. L., Kobor, M. S., & Shilatifard, A. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.07.017 · Cited by 180 · cited 1×
“cerevisiae and human cells [12,37], and a sudden loss of H3K79me2 has been observed during early development in flies and mice [21,38].”
Background
A Chromatin-Dependent Role of the Fragile X Mental Retardation Protein FMRP in the DNA Damage Response
Alpatov, R., Lesch, B. J., Nakamoto-Kinoshita, M., Blanco, M. A., Chen, S., Stützer, A., Armache, K., Simon, M. D., Xu, C., Ali, M., et al. (2014) · Cell · doi:10.1016/j.cell.2014.03.040 · Cited by 175 · cited 2×
“The PWWP (named after a conserved Pro-Trp-Trp-Pro motif) domain of hepatoma-derived growth factor 2 (HDGF2) binds H3K79me3 [70], while the Tudor domain of survival of motor neuron protein (SMN) [71] and the tandem Tudor domains of 53BP1 and fragile X mental retardation protein (FMRP) also bind H3K79me [72,73].”
Background
Nonprocessive methylation by Dot1 leads to functional redundancy of histone H3K79 methylation states
Frederiks, F., Tzouros, M., Oudgenoeg, G., van Welsem, T., Fornerod, M. W. J., Krijgsveld, J., & van Leeuwen, F. (2008) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1432 · Cited by 172 · cited 1×
“Dot1/DOT1L (DOT1-Like) catalyse mono-, di- and tri-methylation of histone H3 lysine 79 in a non-processive manner [17,19] using S-adenosylmethionine (SAM) as a cofactor.”
Method
Function of leukemogenic mixed lineage leukemia 1 (MLL) fusion proteins through distinct partner protein complexes
Biswas, D., Milne, T. A., Basrur, V., Kim, J., Elenitoba‐Johnson, K. S. J., Allis, C. D., & Roeder, R. G. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1111498108 · Cited by 168 · cited 6×
“Complex Protein Components Reference AEP AFF1/4, ENL, P-TEFb [60] AF4-associated AFF1, AF9, DOT1L, ENL, MLLT10, P-TEFb [61] AF9-associated AF9, DOT1L (mutually exclusive with AF4/AFF4, AF9, P-TEFb) [62] DotCom AF9, CTNNB1, DOT1L, ENL, MLLT6, MLLT10, SKP1, TRRAP [63] EAP AFF1/3/4, BCOR, CBX8, DOT1L, ENL, P-TEFb, RING1…”
BackgroundInfluential
Histone modifying enzymes and cancer: Going beyond histones
Zhang, K., & Dent, S. (2005) · Journal of Cellular Biochemistry · doi:10.1002/jcb.20615 · Cited by 157
Genome-wide Profiling of Chromatin Signatures Reveals Epigenetic Regulation of MicroRNA Genes in Colorectal Cancer
Suzuki, H., Takatsuka, S., Akashi, H., Yamamoto, E., Nojima, M., Maruyama, R., Kai, M., Yamano, H., Sasaki, Y., Tokino, T., et al. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-1076 · Cited by 157 · cited 1×
“Furthermore, H3K79me2 is detected at expressed miRNA genes, as well as protein-coding genes [48].”
Background
Reciprocal intronic and exonic histone modification regions in humans
Huff, J. T., Plocik, A. M., Guthrie, C., & Yamamoto, K. R. (2010) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1924 · Cited by 138 · cited 3×
“H3K79me1 peaks in the same region as the diand trimethylation but displays a broader distribution [43,56].”
Background
The many roles of the conserved eukaryotic Paf1 complex in regulating transcription, histone modifications, and disease states
Tomson, B. N., & Arndt, K. M. (2012) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2012.08.011 · Cited by 137 · cited 1×
“The Paf1 complex, associated with elongating RNA polymerase II (RNAPII), enhances the recruitment of Rad6 and Bre1 to chromatin, linking this modification to transcription elongation [23].”
Background
Chatting histone modifications in mammals
Izzo, A., & Schneider, R. (2010) · Briefings in Functional Genomics · doi:10.1093/bfgp/elq024 · Cited by 136 · cited 1×
“Similarly, in humans, monoubiquitination of histone H2B lysine 120 is required for efficient methylation of H3K79 by DOT1L [29].”
Background
Characterization of the grappa Gene, the Drosophila Histone H3 Lysine 79 Methyltransferase
Shanower, G., Müller, M., Blanton, J. L., Honti, V., Gyurkovics, H., & Schedl, P. D. (2004) · Genetics · doi:10.1534/genetics.104.033191 · Cited by 135 · cited 3×
“These are the only known H3K79 methyltransferases, as knockout of their genes in yeast, flies, mice and humans leads to complete loss of H3K79 methylation [13,20,21].”
Background
A charge-based interaction between histone H4 and Dot1 is required for H3K79 methylation and telomere silencing: identification of a new trans-histone pathwayPreprint
Fingerman, I. M., Li, H.-C., & Briggs, S. D. (2007) · Genes & Development · doi:10.1101/gad.1560607 · Cited by 132 · cited 1×
“Conversely, it has been shown that a basic patch on histone H4 is critical for Dot1 binding and H3K79 methylation and that Sir3 competes with Dot1 for the same site on H4 [74,77].”
Background
Histone H2A phosphorylation and H3 methylation are required for a novel Rad9 DSB repair function following checkpoint activation
Toh, G. W. ‐., O'Shaughnessy, A. M., Jimeno, S., Dobbie, I. M., Grenon, M., Maffini, S., O’Rorke, A., & Lowndes, N. F. (2006) · DNA repair · doi:10.1016/j.dnarep.2006.03.005 · Cited by 123 · cited 1×
“While Dot1 deletion mutants do not show a G2 arrest phenotype [85], Rad9 recruitment to sites of DNA damage and phosphorylation of Rad53, a downstream transducer protein (see Figure 4), following IR treatment still requires Dot1 [87].”
Background
The emerging roles of DOT1L in leukemia and normal development
McLean, C. M., Karemaker, I. D., & van Leeuwen, F. (2014) · Leukemia · doi:10.1038/leu.2014.169 · Cited by 118 · cited 1×
“It is worth noting that DOT1L is extremely important in development [105] and a large proportion of MLL-linked leukaemia patients are infants [106], making alternative treatment options all the more important.”
Background
Dot1 and Histone H3K79 Methylation in Natural Telomeric and HM Silencing
Takahashi, Y.-H., Schulze-Hentrich, J. M., Jackson, J., Hentrich, T., Seidel, C. W., Jaspersen, S. L., Kobor, M. S., & Shilatifard, A. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.03.006 · Cited by 116 · cited 1×
“[79] also demonstrated that the role of Dot1 in heterochromatin formation is telomere-specific.”
Background
Leukemia Fusion Target AF9 Is an Intrinsically Disordered Transcriptional Regulator that Recruits Multiple Partners via Coupled Folding and Binding
Leach, B. I., Kuntimaddi, A., Schmidt, C., Cierpicki, T., Johnson, S. A., & Bushweller, J. H. (2012) · Structure · doi:10.1016/j.str.2012.11.011 · Cited by 114 · cited 2×
“The reason behind this is the binding of DOT1L and AF4 to the same intrinsically disordered domain of AF9/ENL [68].”
Background
Bat3 facilitates H3K79 dimethylation by DOT1L and promotes DNA damage‐induced 53BP1 foci at G1/G2 cell‐cycle phases
Wakeman, T. P., Wang, Q., Feng, J., & Wang, X. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.50 · Cited by 113 · cited 4×
“Similarly, studies in mammalian cells have demonstrated that knockdown of DOT1L increases sensitivity to IR and UV radiation [53,96,97].”
BackgroundInfluential
Docking onto chromatin via the Saccharomyces cerevisiae Rad9 Tudor domain
Grenon, M., Costelloe, T., Jimeno, S., O'Shaughnessy, A. M., Fitzgerald, J., Zgheib, O., Degerth, L., & Lowndes, N. F. (2007) · Yeast · doi:10.1002/yea.1441 · Cited by 110
Human Histone H3K79 Methyltransferase DOT1L Methyltransferase Binds Actively Transcribing RNA Polymerase II to Regulate Gene Expression
Kim, S.-K., Jung, I., Lee, H., Kang, K., Kim, M., Jeong, K., Kwon, C. S., Han, Y., Kim, Y. S., Kim, D., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.384057 · Cited by 108
Changes in H3K79 Methylation During Preimplantation Development in Mice
Ooga, M., Inoue, A., Kageyama, S., Akiyama, T., Nagata, M., & Aoki, F. (2007) · Biology of Reproduction · doi:10.1095/biolreprod.107.063453 · Cited by 105 · cited 1×
“cerevisiae and human cells [12,37], and a sudden loss of H3K79me2 has been observed during early development in flies and mice [21,38].”
Background
Methylation of histone H3 lysine-79 by Dot1p plays multiple roles in the response to UV damage in Saccharomyces cerevisiae
Bostelman, L. J., Keller, A. M., Albrecht, A. M., Arat, A., & Thompson, J. S. (2007) · DNA repair · doi:10.1016/j.dnarep.2006.12.010 · Cited by 85 · cited 3×
“Dot in NER is supported by the similarity in the UV survival pattern of a dot1Δ, rad1Δ a d dot1Δ rad1Δ yeast strain [91].”
Background
Nonclinical pharmacokinetics and metabolism of EPZ‐5676, a novel DOT1L histone methyltransferase inhibitor
Basavapathruni, A., Olhava, E. J., Daigle, S. R., Therkelsen, C. A., Jin, L., Boriack‐Sjodin, P. A., Allain, C. J., Klaus, C. R., Raimondi, A., Scott, M. P., et al. (2014) · Biopharmaceutics & Drug Disposition · doi:10.1002/bdd.1889 · Cited by 79 · cited 1×
“A second-generation inhibitor, EPZ5676, is currently in clinical trials for the treatment of MLL-rearranged leukemias, and while the results look promising [102], the low bioavailability of the drug is a complicating factor [103].”
Background
Histone Methyltransferase DOT1L Drives Recovery of Gene Expression after a Genotoxic Attack
Oksenych, V., Zhovmer, A. S., Ziani, S., Mari, P., Eberová, J., Nardò, T., Stefanini, M., Giglia‐Mari, G., Egly, J., & Coin, F. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003611 · Cited by 78 · cited 2×
“Similarly, studies in mammalian cells have demonstrated that knockdown of DOT1L increases sensitivity to IR and UV radiation [53,96,97].”
Background
DOT1L Inhibition Sensitizes MLL-Rearranged AML to Chemotherapy
Liu, W., Deng, L., Song, Y., & Redell, M. S. (2014) · PLoS ONE · doi:10.1371/journal.pone.0098270 · Cited by 76 · cited 1×
“Two other recent small molecules targeting DOT1L with high specificity have also been developed, SGC0946 and SYC-522 [101,104].”
Background
H2B monoubiquitylation is a 5′-enriched active transcription mark and correlates with exon–intron structure in human cellsPreprint
Jung, I., Kim, S.-K., Kim, M., Han, Y., Kim, Y. S., Kim, D., & Lee, D. (2012) · Genome Research · doi:10.1101/gr.120634.111 · Cited by 69 · cited 2×
“Representative genome browser track of read coverage profiles of RNA polymerase II (RNAPII) Ser5P (initiation complex), DOT1L and different histone marks (ubiquitination of histone 2B lysine 120 (H2BK120ub), histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 36 trimethylation (H3K36me3), histone 3 lysine 79…”
Background
Mixed lineage rearranged leukaemia
Stein, E. M., & Tallman, M. S. (2015) · Current Opinion in Hematology · doi:10.1097/moh.0000000000000123 · Cited by 69 · cited 1×
“A second-generation inhibitor, EPZ5676, is currently in clinical trials for the treatment of MLL-rearranged leukemias, and while the results look promising [102], the low bioavailability of the drug is a complicating factor [103].”
Background
The RAD6/BRE1 Histone Modification Pathway in Saccharomyces Confers Radiation Resistance Through a RAD51-Dependent Process That Is Independent of RAD18
Game, J. C., Williamson, M. S., Spicakova, T., & Brown, J. M. (2006) · Genetics · doi:10.1534/genetics.106.057794 · Cited by 67 · cited 12×
“In addition to its G1 checkpoint role, it has been shown that Dot1 confers IR-resistance mediated by promoting homologous recombination (HR) repair of DSBs [85].”
BackgroundInfluential
A Common Telomeric Gene Silencing Assay Is Affected by Nucleotide Metabolism
Rossmann, M. P., Luo, W., Tsaponina, O., Chabes, A., & Stillman, B. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.03.007 · Cited by 66 · cited 1×
“[78] showed, using a URA3 telomere reporter assay, that the silencing defect in Dot1 mutants is rather due to an imbalance in ribonucleotide reductase and a URA3 promoter at telomere VII-L rather than a need for Dot1 in general telomere silencing.”
Method
Global reduction of the epigenetic H3K79 methylation mark and increased chromosomal instability in CALM-AF10–positive leukemias
Lin, Y.-H., Kakadia, P. M., Chen, Y., Li, Y.-Q., Deshpande, A. J., Buske, C., Zhang, K.-L., Zhang, Y., Xu, G.-L., & Bohlander, S. K. (2009) · Blood · doi:10.1182/blood-2009-03-209395 · Cited by 64 · cited 2×
“Similarly, studies in mammalian cells have demonstrated that knockdown of DOT1L increases sensitivity to IR and UV radiation [53,96,97].”
Background
The Dot1 Histone Methyltransferase and the Rad9 Checkpoint Adaptor Contribute to Cohesin-Dependent Double-Strand Break Repair by Sister Chromatid Recombination in Saccharomyces cerevisiae
Conde, F., Refolio, E., Cordón-Preciado, V., Cortés‐Ledesma, F., Aragón, L., Aguilera, A., & San-Segundo, P. A. (2009) · Genetics · doi:10.1534/genetics.109.101899 · Cited by 64 · cited 3×
“Proteins such as cohesin are essential for maintaining chromosome structure and efficient SCR, and not only does Dot1 have an essential role in the recruitment of Rad9 to DSBs for DNA resection, it also promotes the recruitment of cohesin for efficient SCR [90].”
Background
Silent information regulator 3: the Goldilocks of the silencing complexPreprint
Norris, A., & Boeke, J. D. (2010) · Genes & Development · doi:10.1101/gad.1865510 · Cited by 62 · cited 1×
“Telomeric and telomere-proximal DNA silencing is established via the recruitment and binding of Sir (silent information regulator) proteins [76].”
Background
Deficiency in Bre1 Impairs Homologous Recombination Repair and Cell Cycle Checkpoint Response to Radiation Damage in Mammalian Cells
Chernikova, S. B., Dorth, J. A., Razorenova, O. V., Game, J. C., & Brown, J. M. (2010) · Radiation Research · doi:10.1667/rr2184.1 · Cited by 60
DNA-histone interactions in nucleosomes
Holde, K. E. V., Allen, J., Tatchell, K., Weischet, W. O., & Lohr, D. (1980) · Biophysical Journal · doi:10.1016/s0006-3495(80)84956-3 · Cited by 53
Role of Dot1 in the Response to Alkylating DNA Damage in Saccharomyces cerevisiae: Regulation of DNA Damage Tolerance by the Error-Prone Polymerases Polζ/Rev1
Conde, F., & San-Segundo, P. A. (2008) · Genetics · doi:10.1534/genetics.108.089003 · Cited by 51
Epigenetic mechanisms in human disease.
Feinberg, A. P., Oshimura, M., & Barrett, J. C. (2002) · PubMed · Cited by 47
The Mediator subunit MED23 couples H2B mono‐ubiquitination to transcriptional control and cell fate determination
Xiao, Y., Tang, Z., Fu, X., Yin, J., Liang, Y., Li, C., Li, H., Tian, Q., Roeder, R. G., & Wang, G. (2015) · The EMBO Journal · doi:10.15252/embj.201591279 · Cited by 46
The tudor protein survival motor neuron (SMN) is a chromatin-binding protein that interacts with methylated histone H3 lysine 79
Sabra, M., Texier, P., Maalouf, J. E., & Lomonte, P. (2013) · Journal of Cell Science · doi:10.1242/jcs.126003 · Cited by 43
Regulation of tolerance to DNA alkylating damage by Dot1 and Rad53 in Saccharomyces cerevisiae
Conde, F., Ontoso, D., Acosta, I., Gallego-Sánchez, A., Bueno, A., & San-Segundo, P. A. (2010) · DNA repair · doi:10.1016/j.dnarep.2010.07.003 · Cited by 40
Structural Plasticity of Methyllysine Recognition by the Tandem Tudor Domain of 53BP1
Tong, Q., Cui, G., Botuyan, M. V., Rothbart, S. B., Hayashi, R., Musselman, C. A., Singh, N., Appella, E., Strahl, B. D., Mer, G., et al. (2015) · Structure · doi:10.1016/j.str.2014.11.013 · Cited by 39
DOT1L-Mediated H3K79 Methylation in Chromatin Is Dispensable for Wnt Pathway-Specific and Other Intestinal Epithelial Functions
Ho, L., Sinha, A., Verzi, M. P., Bernt, K. M., Armstrong, S. A., & Shivdasani, R. A. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01463-12 · Cited by 38 · cited 2×
“However, another study performed in mouse intestinal epithelia found that DOT1L and H3K79me2 w e not requir d for the expression of Wingless target g nes, questioning the requiremen f DOT1L for the Wnt pathway in mammals [67].”
Background
Loss of H3 K79 Trimethylation Leads to Suppression of Rtt107-dependent DNA Damage Sensitivity through the Translesion Synthesis Pathway
Lévesque, N., Leung, G. P., Fok, A. K., Schmidt, T. I., & Kobor, M. S. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.116855 · Cited by 36

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The roles of DNA, RNA and histone methylation in ageing and cancer
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Targeting Transcription Factors for Cancer Treatment
Lambert, M., Jambon, S., Depauw, S., & David‐Cordonnier, M. (2018) · Molecules · doi:10.3390/molecules23061479 · Cited by 359
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Yang, Q., Jiang, W., & Hou, P. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.04.001 · Cited by 210
Structural Basis of Dot1L Stimulation by Histone H2B Lysine 120 Ubiquitination
Valencia‐Sánchez, M. I., Ioannes, P. D., Wang, M., Vasilyev, N., Chen, R., Nudler, E., Armache, J., & Armache, K. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.03.029 · Cited by 150
“Dot1L associates with proteins involved in transcription elongation, as well as RNA pol II, and transcription elongation rates are positively correlated with H3K79 methylation (Bitoun et al., 2007; Kim et al., 2012; Kouskouti and Talianidis, 2005; Krogan et al., 2003; Mohan et al., 2010; Mueller et al., 2007; Steger e…”
Quercetin modifies 5′CpG promoter methylation and reactivates various tumor suppressor genes by modulating epigenetic marks in human cervical cancer cells
Sundaram, M. K., Hussain, A., Haque, S., Raina, R., & Afroze, N. (2019) · Journal of Cellular Biochemistry · doi:10.1002/jcb.29147 · Cited by 142

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Authors: Wood, K., Tellier, M., & Murphy, S.
Affiliations: University of Manchester (GB)
University of Oxford (GB)
Corresponding author: Tellier, Michael
Murphy, Shona
ORCID: Wood, Katherine
Tellier, Michael
Murphy, Shona
Venue: Biomolecules
Publisher: MDPI AG
Published: 2018-02-27
Volume: 8
Issue: 1
Pages: 11
ISSN: 2218-273X (ISSN-L)
DOI: 10.3390/biom8010011
PMC: PMC5871980
OpenAlex: W2791712220
Cited by: 209
References: 110
Citations by year: 2026: 18 · 2025: 23 · 2024: 23 · 2023: 18 · 2022: 34 · 2021: 33 · 2020: 27 · 2019: 28 · 2018: 5
FWCI: 2.33
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Biomolecules (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: Wellcome Trust (WT106134AIA)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
Keywords: DOT1L, H3K79 methylation, histone methyltransferase, chromatin organization, transcription elongation, RNA polymerase II, DNA damage response, cell cycle checkpoints, genome stability, MLL-rearranged leukemia, histone modifications
MeSH terms: Animals, Histones, Humans, Histone-Lysine N-Methyltransferase, Yeasts, Histone Code, Genomic Instability, Transcription Elongation, Genetic

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DOT1L and H3K79 Methylation in Transcription and Genomic Stability

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