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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Caldwell, B. A., Wu, Y., Wang, J., & Li, L. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.08.30.555580 · Cited by 2
The histone methyltransferase DOT1B is dispensable for stage differentiation and macrophage infection in Leishmania mexicanaPreprint
Eisenhuth, N., Rauh, E. T., Mitnacht, M., Debus, A., Butter, F., Schleicher, U., Pružinová, K., Volf, P., & Janzen, C. J. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.11.612422 · Cited by 2
Shared Genetic Features of Psoriasis and Myocardial Infarction: Insights From a Weighted Gene Coexpression Network Analysis
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“26,29 31–34 It is important to highlight that DOT1L inhibition effectively mitigates renal fibrosis in cases of ischemia and reperfusion injury through the PI3K/AKT pathway.”
Background
The H3K79me3 methyl-transferase Grappa is involved in the establishment and thermal plasticity of abdominal pigmentation in Drosophila melanogaster females
Narbey, R., Mouchel‐Vielh, E., & Gibert, J. (2024) · Scientific Reports · doi:10.1038/s41598-024-60184-6 · Cited by 1
“In human, these methylations are associated with activation at single-copy genes 21 .”
Background
Unraveling gene expression: a beginner’s guide from chromatin modifications to mRNA export in Saccharomyces cerevisiae
Serrano‐Quílez, J., & Rodríguez‐Navarro, S. (2025) · Nucleus · doi:10.1080/19491034.2025.2516909 · Cited by 1
“To date, no demethylase for H3K79 has been identified in yeast [96].”
Elucidating the risk factors and oncogene drivers of acute myeloid leukemia
Sanya, D. R. A., & Onésime, D. (2025) · Human Cell · doi:10.1007/s13577-025-01294-9 · Cited by 1
Inhibition of H3K79me2 by DOT1L Inhibitor EPZ5676 Promotes Mouse Embryonic Lung Branching Morphogenesis via Increasing Epithelium Proliferation
Du, Y., Pan, M., Chen, H., Zhang, R., Cai, B., Xu, D., Li, Y., He, W., Liu, S., Zhou, C., et al. (2025) · The FASEB Journal · doi:10.1096/fj.202502302r · Cited by 1
“H3K79 methylation was catalyzed specifically by DOT1L, the only known enzyme in mammals that can catalyze this modification [6, 19].”
Inhibition of Methyltransferase DOT1L alleviates anti-tuberculosis drug-induced liver injury by inhibiting p53-Bax/Bcl-2 pathway
Li, J., Pei, S., Dongxue, W., Yifei, L., Qirong, W., & Fumin, F. (2025) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2025.178415 · Cited by 1
Trypanosome histone variants H3.V and H4.V promote nucleosome plasticity in repressed chromatin
Deák, G., Burdett, H., Watson, J. A., & Wilson, M. D. (2026) · Structure · doi:10.1016/j.str.2026.01.008 · Cited by 1
Histone methyltransferase DOT1L differentially affects the development of dendritic cell subsets
Bouma, R. G., de Leeuw, W.-J., Wang, A. Z., Malik, M., Stolwijk, J. G. C., Konijn, V. A. L., Mensink, A., Proost, N., Twilhaar, M. K. N., van Welsem, T., et al. (2026) · Life Science Alliance · doi:10.26508/lsa.202603624 · Cited by 1
Post-translational modifications in retinoblastoma: mechanisms, immune regulation, and therapeutic opportunities
Xu, L., Wang, B., Li, W., Luo, X., Wang, L., & Zheng, Y. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1820785 · Cited by 1
A novel role of DOT1L in kidney diseases
Wei, W., Zhao, Y., Chai, Y., Shou, S., & Jin, H. (2023) · Molecular Biology Reports · doi:10.1007/s11033-023-08415-3 · Cited by 1
“DOT1L is a relatively evolutionarily-conserved histone methyltransferase that does not contain the SET domain [10].”
Background
Protein phase separation disorder as a potentially pervasive pathogenic mechanism of male infertility
Geng, J., Feng, W., Liu, Y., Li, J., Gao, H., & Wu, B. (2023) · Medical Hypotheses · doi:10.1016/j.mehy.2023.111189 · Cited by 1
Histone modifications
Morse, R. H. (2024) · Elsevier eBooks · doi:10.1016/b978-0-12-814809-9.00002-0 · Cited by 1
The role of chromatin-related epigenetic modulations in CAKUT
König, L., & Schmidts, M. (2025) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2024.11.006 · Cited by 1
ICGEC: a comparative method for measuring epigenetic conservation of genes via the integrated signal from multiple histone modifications between cell types
Tang, J. Y., Wu, Z., Tian, Y., & Yang, R. (2020) · BMC Genomics · doi:10.1186/s12864-020-6771-1 · Cited by 1
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Background
Modulating Epigenetic Modification Enzymes Through Relevant Epidrugs as a Timely Strategy in Anticancer Therapy
Ganai, S. A. (2020) · Springer eBooks · doi:10.1007/978-981-15-8179-3_7 · Cited by 1
DOT1L Methyltransferase Activity Preserves SOX2-Enhancer Accessibility And Prevents Activation of Repressed Genes In Murine Stem CellsPreprint
Ferrari, F. D. B., Arrigoni, L., Franz, H., Butenko, L., Trompouki, E., Vogel, T., & Manke, T. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.02.03.931741 · Cited by 1
DOT1L stimulates MYC/Mondo transcription factor activity by promoting its degradation cycle on chromatinPreprint
Sepulveda, G. P., Gushchanskaia, E. S., Mora-Martin, A., Esse, R., Nikorich, I., Ceballos, A., Kwan, J., Blum, B. C., Dholiya, P., Emili, A., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.02.06.579191 · Cited by 1
Epigenetic Profiling of Neuroactive Curcumin on Histone Signatures in Breast Cancer using gen3DNet
Tang, T., Berezin, M. Y., Garcia, B. A., & Mollah, S. A. (2026) · Cancer Treatment and Research Communications · doi:10.1101/2024.11.13.623008 · Cited by 1
“The second histone mark, H3K79me1, is associated with transcriptional activation along with its counterparts, H3K79me2/3 (43, 44).”
Structural basis for activation of Dot1L methyltransferase on the nucleosome by histone H2BK120 ubiquitylationPreprint
Anderson, C. J., Baird, M. R., Hsu, A. L., Barbour, E. H., Koyama, Y., Borgnia, M. J., & McGinty, R. K. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/503128
“While known to participate in several transcriptional elongation complexes (Wood et al., 2018), Dot1L can bind to and methylate H3K79 in nucleosomes in isolation (Feng”
Background
DOT1L Epigenetically Induces the Expression Level of FoxM1 through H3K79me2 and Affects the Malignant Behaviors of Head and Neck Squamous Cell Carcinoma Cells
Du, H., & Zhang, L. (2022) · Journal of Hard Tissue Biology · doi:10.2485/jhtb.31.101
Loss of the Ash2l subunit of histone H3K4 methyltransferase complexes promotes chromatin compaction at promotersPreprint
Barsoum, M., Stenzel, A. T., Bochyńska, A., Kuo, C., Sayadi-Boroujeni, R., Bussmann, P., Lüscher‐Firzlaff, J., Costa, I. G., & Lüscher, B. (2022) · Research Square · doi:10.21203/rs.3.rs-1992778/v1
Additional file 2 of ICGEC: a comparative method for measuring epigenetic conservation of genes via the integrated signal from multiple histone modifications between cell types
Tang, J. P., Wu, Z., Tian, Y., & Yang, R. (2020) · Figshare · doi:10.6084/m9.figshare.12291728
Histone Lysine Methyltransferases
O’Donovan, D. H., Hsu, J. J., Liu, H., & Read, J. A. (2024) · Royal Society of Chemistry eBooks · doi:10.1039/9781837674916-00307
Drug Discovery for Chromatin Readers, Writers, Erasers, Remodelers and Epitranscriptomic Targets
(2024) · Royal Society of Chemistry eBooks · doi:10.1039/9781837674916-part3
Study on DNA Damage Gene in Spermatogonial Stem Cells from Idiopathic Nonobstructive Azoospermia: A Bioinformatics Investigation Based on scRNA-seq Data
Wang, Y., Weng, Y., Wang, Y., Xiang, J., & Le, W. (2025) · Cytogenetic and Genome Research · doi:10.1159/000545275
“The DNA repair mechanism of SSCs is disrupted, and the accumulated DNA damage interferes with the self-renewal and differentiation processes of SSCs, dimethylation, and trimethylation of H3K79 using SAM as a methyl donor [23], and H3K79 methylation is associated with active transcription [24, 25].”
Lysosomes Signal through Epigenome to Regulate Longevity across GenerationsPreprint
Zhang, Q., Dang, W., & Wang, M. C. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.05.21.652954
Dysregulation of an H3K79me2-dependent epigenetic barrier impairs neural progenitor cell proliferation and differentiation in Fragile X syndromePreprint
Dionne, O., Gaudreau, G.-L., Bergis, C., Avino, M., Sabatié, S., Corbin, F., & Laurent, B. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.31.673358
Delineating plant responses to the 3’,5’- and 2’,3’-cAMP isomersPreprint
Davide, E., Domingo, G., Iacovo, A. D., Marsoni, M., Yun, P., Gehring, C., Bossi, E., Shabala, S. N., Bracale, M., & Vannini, C. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.09.681331
Additional file 1 of ICGEC: a comparative method for measuring epigenetic conservation of genes via the integrated signal from multiple histone modifications between cell types
Tang, J., Wu, Z., Tian, Y., & Yang, R. (2020) · Figshare · doi:10.6084/m9.figshare.12291722
Case report and literature review of neurodevelopmental syndrome linked to DOT1L variants
Caux, A., Jobic, F., Keren, B., Billes, A., Magry, V., L’Haridon, A., Darwiche, W., Jedraszak, G., & Gilles, M. (2025) · Gene · doi:10.1016/j.gene.2025.149987
Bacterial targeting of host paraspeckles uncovers a new SFPQ-based regulationPreprint
Nicchi, S., Mondino, S., Rusniok, C., Mahtal, N., Raynal, B. D. E., Elj, R., Gianetto, Q. G., Rizza, J. D., Larrieux, N., Martyn, J. E., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.11.698932
“We named it LpDot1 due to its homology with the catalytic domain of the eukaryotic DOT1 (Disruptor of Telomeric Silencing-1) reported to exclusively methylate lysine K79 in the globular region of histone H3, affecting gene expression and DNA damage response 22 .”
PICALM :: MLLT10 translocated leukemia
Cullen, J. M., Nakatsugawa, A. C., Barton, N., Haines, H., Stein, G. S., Stein, J. L., Wechsler, D. S., & Heath, J. L. (2026) · FEBS Letters · doi:10.1002/1873-3468.70279
“In addition to transcription, DNA repair, cell cycle regulation, and development, DOT1L is vital for embryonic and adult hematopoiesis and has been implicated in leukemogenesis [47 – 53].”
Distinct chromatin regulators downmodulate meiotic axis protein deposition and DNA break induction at chromosome endsPreprint
Raghavan, A. R., May, K., Subramanian, V. V., Blitzblau, H. G., Patel, N. J., Houseley, J. M., & Hochwagen, A. (2026) · eLife · doi:10.7554/elife.110189.1
Separable downmodulation of meiotic axis protein deposition and DNA break induction at chromosome endsPreprint
Raghavan, A. R., May, K., Subramanian, V. V., Blitzblau, H. G., Patel, N. J., Houseley, J. M., & Hochwagen, A. (2026) · eLife · doi:10.7554/elife.110189
“In vegetative cells, Dot1 helps constrain Sir-protein dependent silencing both through H3K79 trimethylation and by competing for the same nucleosomal binding site ( Wood et al., 2018 ).”
Heterochromatin dynamics upon release from stationary phase in budding yeast
Galić, H. (2019) · doi:10.70675/91991937z0bb5z433bz86e8z179f21d3d624
Effets des métabolites réactifs du benzène et d'une mutation oncogénique sur SetD2, une histone méthyltransférase
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Metabolic imprint induces histone hypermethylation during Chlamydia trachomatis infection
Charendoff, C. I. (2021) · doi:10.70675/e68c5753z858bz4d57z88e6z3a1d79eb3134

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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