Affinage

DOT1L

Histone-lysine N-methyltransferase, H3 lysine-79 specific · UniProt Q8TEK3

Length
1537 aa
Mass
164.9 kDa
Annotated
2026-04-28
100 papers in source corpus 39 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DOT1L is the sole histone H3 lysine 79 methyltransferase, catalyzing mono-, di-, and trimethylation of H3K79 within the nucleosome core to regulate transcription, DNA damage repair, and cell fate decisions across diverse lineages (PMID:12080090, PMID:18285465). Its catalytic processivity is allosterically stimulated by H2B monoubiquitylation—via direct ubiquitin–DOT1L contacts at H2BK120 or via nucleosome distortion at H2BK34—and by H4K16 acetylation, while H3T11 phosphorylation inhibits chromatin binding (PMID:30759380, PMID:35739357, PMID:33479126, PMID:36473858). DOT1L is recruited to target loci through interactions with AF9/ENL (via a conserved 10-residue motif), AF10 (via a zinc-stabilized coiled-coil interface), β-catenin/TCF4 complexes, and other transcription factors including Zc3h10 and nuclear receptors, and possesses a catalytic-independent scaffolding role in transcription elongation (PMID:23996074, PMID:29563185, PMID:21103407, PMID:33107819, PMID:33077595). H3K79 methylation marks facilitate DNA damage checkpoint signaling by enabling 53BP1/Rad9 recruitment and nucleotide excision repair via XPC recruitment, while mislocalization of DOT1L by MLL-fusion oncoproteins drives aberrant HOXA gene activation and leukemogenesis (PMID:16166626, PMID:29343685, PMID:26927674).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2002 High

    The discovery that Dot1 methylates H3K79 in the nucleosome globular domain—and that this mark controls telomeric silencing by regulating Sir protein occupancy—established a new class of histone modification outside the N-terminal tails and linked it to chromatin domain organization.

    Evidence Genetic mutagenesis of H3K79 and Dot1 catalytic residues; mass spectrometry; ChIP of Sir proteins in S. cerevisiae

    PMID:12080090

    Open questions at the time
    • Mechanism by which H3K79me excludes Sir proteins was unclear
    • Mammalian ortholog function not yet tested
    • Enzyme processivity and methylation state regulation unknown
  2. 2005 High

    Demonstration that H2B ubiquitylation controls the transition from H3K79 mono- to di/trimethylation—without affecting Dot1 recruitment—established trans-histone crosstalk as a processivity switch rather than a recruitment mechanism, and that H3K79me functions in DNA damage checkpoint activation upstream of Rad9/53BP1.

    Evidence ChIP, mass spectrometry, and Rad6-Bre1 pathway genetics in yeast; epistasis analysis of checkpoint kinases; human 53BP1 recruitment assays

    PMID:15632126 PMID:16039595 PMID:16166626

    Open questions at the time
    • Structural basis of ubiquitin-Dot1 contact unknown
    • Whether H2Bub stimulation is conserved in mammals not resolved
    • Mechanism of 53BP1 tudor domain recognition of H3K79me not structurally defined
  3. 2008 High

    Genome-wide mapping in mammalian cells demonstrated that DOT1L is the sole H3K79 methyltransferase, is ubiquitously associated with active transcription, and preferentially occupies proximal coding regions—redefining H3K79me as a general mark of transcriptional activity rather than a silencing-specific modification.

    Evidence ChIP-chip tiling arrays in wild-type and Dot1l-null mouse fibroblasts

    PMID:18285465

    Open questions at the time
    • Whether DOT1L has catalytic-independent transcriptional roles unknown
    • Context-specific gene regulatory programs not yet dissected
  4. 2010 High

    Purification of the DotCom complex revealed that DOT1L partners with MLL-fusion proteins (AF9, ENL, AF10, AF17) and Wnt signaling components (β-catenin, Skp1), and that DOT1L is recruited to Wnt target genes via β-catenin/TCF4-AF10 interaction to activate transcription—linking H3K79 methylation to a major developmental signaling pathway.

    Evidence Affinity purification/MS of DotCom; Drosophila Wingless RNAi; proteomics and ChIP in mouse intestinal crypts; zebrafish apc epistasis

    PMID:20203130 PMID:20431927 PMID:21103407

    Open questions at the time
    • Structural basis of DOT1L-AF10 interaction not resolved
    • Relative contributions of individual complex members to targeting unclear
  5. 2011 High

    Conditional cardiac knockout showed DOT1L is required for Dystrophin transcription and heart function, while yeast Dot1 was shown to facilitate global genomic repair independently of checkpoint activation—demonstrating that H3K79me has tissue-specific transcriptional targets and distinct roles in DNA repair sub-pathways.

    Evidence Cardiac-specific Dot1L knockout with miniDmd rescue in mice; UV-induced NER assays and epistasis in yeast

    PMID:21289070 PMID:21460225

    Open questions at the time
    • Whether DOT1L regulates cardiomyocyte gene networks beyond Dmd unknown
    • GGR chromatin docking factor for H3K79me not identified
  6. 2012 High

    Crystal structures of DOT1L with SAM-competitive inhibitors revealed a conformational adaptation mechanism in the active site that explains slow inhibitor dissociation kinetics and provided a template for drug design.

    Evidence X-ray crystallography with aminonucleoside inhibitors; enzyme kinetics

    PMID:22978415 PMID:23433670

    Open questions at the time
    • No structure of DOT1L bound to nucleosome substrate yet
    • Catalytic mechanism of methyl transfer not fully resolved
  7. 2013 High

    Mapping of the DOT1L-AF9/ENL interaction to a 10-amino-acid motif essential for MLL-AF9-driven leukemic transformation, together with the finding that H3K79me activates the meiotic checkpoint kinase Mek1 via Hop1 redistribution, defined the molecular determinants of DOT1L recruitment in leukemogenesis and revealed a conserved checkpoint function in meiosis.

    Evidence Alanine scanning mutagenesis and biophysical binding assays; immortalization assays; meiotic checkpoint and Hop1/Pch2 localization in yeast

    PMID:23382701 PMID:23996074

    Open questions at the time
    • Structural basis of DOT1L-AF9 interaction not yet solved
    • Whether meiotic checkpoint role is conserved in mammals unknown
  8. 2014 High

    The discovery that AF9's YEATS domain reads H3K9 acetylation and genome-wide co-localization of AF9 with H3K9ac directs DOT1L recruitment established a histone crosstalk cascade: H3K9ac → AF9 YEATS → DOT1L → H3K79me.

    Evidence Crystal structure of AF9 YEATS–H3K9ac peptide; ChIP-seq; mutagenesis

    PMID:25417107

    Open questions at the time
    • Whether this recruitment mechanism is dominant over other targeting pathways unclear
    • Relative contribution of YEATS reading vs. other interaction modes not quantified
  9. 2016 High

    Quantitative proteomics and ChIP demonstrated that DOT1L-mediated H3K79me2 facilitates H4 acetylation and subsequent BRD4 binding at superenhancer-proximal genes, establishing a functional interdependence between DOT1L and BRD4 in transcription despite their residing in separate complexes.

    Evidence Quantitative proteomics; chemoproteomics; ChIP after pharmacological inhibition in MLL leukemia cells

    PMID:27294782

    Open questions at the time
    • Mechanism by which H3K79me2 promotes H4 acetylation not identified
    • Generality beyond MLL leukemia contexts not tested
  10. 2018 High

    Crystal structures of the DOT1L-AF10 interface showed zinc-stabilized coiled-coil binding and that disruption of this interface blocks MLL-AF10 leukemogenesis; separately, DOT1L was shown to recruit XPC to UV damage sites for nucleotide excision repair, with melanoma-associated DOT1L mutations compromising this function.

    Evidence X-ray crystallography of DOT1L-AF10 complex; mutagenesis and transformation assays; ChIP of XPC at damage sites; Dot1L-knockout mice exposed to UV

    PMID:29343685 PMID:29563185

    Open questions at the time
    • Whether DOT1L-AF10 disruption is therapeutically viable in patients unknown
    • Full spectrum of DOT1L mutations affecting NER not characterized
  11. 2019 High

    Cryo-EM of DOT1L on H2BK120ub nucleosomes provided the first structural view of how ubiquitin directly contacts DOT1L through complementary hydrophobic surfaces and how DOT1L engages the nucleosome acidic patch via an arginine anchor, giving the atomic-level mechanism for trans-histone crosstalk.

    Evidence Cryo-EM of reconstituted DOT1L–H2BK120ub nucleosome complex

    PMID:30759380

    Open questions at the time
    • Dynamics of catalytic cycle on the nucleosome not captured
    • How multiple allosteric inputs (H4K16ac, H2Bub) integrate structurally unknown
  12. 2020 High

    A direct comparison of DOT1L knockout versus catalytically dead knock-in revealed a catalytic-independent role for DOT1L in transcription elongation and neural progenitor fate determination, separating the protein's scaffolding function from its enzymatic activity; concurrently, multiple conditional knockouts showed DOT1L controls T cell, brown adipocyte, and macrophage cell fate programs through locus-specific H3K79me deposition.

    Evidence KO vs catalytic-dead ESC models; super elongation complex inhibitor treatment; conditional Dot1L knockouts in T cells, brown fat (Ucp1-Cre), and myeloid cells; transcriptomics and epigenomics

    PMID:32764145 PMID:33077595 PMID:33107819 PMID:36417856

    Open questions at the time
    • Mechanism of catalytic-independent elongation function unknown
    • How DOT1L achieves locus specificity in different lineages remains unclear
    • Whether scaffolding and enzymatic roles are separable in vivo at endogenous expression levels not tested
  13. 2021 High

    H4K16 acetylation was identified as a distinct allosteric activator of Dot1 that cooperates with but is mechanistically separable from H2Bub stimulation, while DOT1L was shown to be essential for germinal center B cell differentiation by supporting a pro-proliferative program and indirectly maintaining PRC2-mediated repression.

    Evidence In vitro reconstitution with defined histone modifications; ChIP in yeast H4K16 mutants; B cell-specific Dot1L conditional knockout with epigenomics

    PMID:33410591 PMID:33479126

    Open questions at the time
    • Structural basis for H4K16ac allosteric activation not resolved
    • Whether H4K16ac stimulation is conserved in mammalian DOT1L not tested
  14. 2022 High

    Cryo-EM of Dot1L on H2BK34ub nucleosomes revealed a second, structurally distinct mechanism of ubiquitin-dependent activation—nucleosome distortion rather than direct protein contact—while tissue-specific studies showed DOT1L maintains spermatogonial stem cells via HoxC genes, regulates pericentromeric heterochromatin via H3K79me3 at satellite repeats, and controls context-specific cardiogenic gene networks including postnatal cell cycle withdrawal.

    Evidence Cryo-EM of H2BK34ub nucleosome ± Dot1L; conditional knockouts in germ cells, ESCs/embryos, and embryonic cardiomyocytes; ChIP-seq distinguishing H3K79me2/me3

    PMID:35738678 PMID:35739357 PMID:36460641 PMID:37317657

    Open questions at the time
    • How H2BK34ub and H2BK120ub stimulation are coordinated in vivo unknown
    • Whether DOT1L has additional catalytic-independent roles in heterochromatin not tested
    • Upstream signals directing H3K79me2 vs me3 deposition at different loci unresolved
  15. 2022 High

    CBP-mediated acetylation of DOT1L at K358 was shown to prevent RNF8-dependent proteasomal degradation, establishing a post-translational regulatory axis that stabilizes DOT1L protein levels and promotes epithelial-mesenchymal transition via H3K79 methylation at SNAIL and ZEB1 promoters; concurrently, H3T11 phosphorylation by pyruvate kinase was identified as an inhibitory mark that reduces Dot1 chromatin binding and H3K79me3.

    Evidence MS identification of K358 acetylation; co-IP of RNF8-DOT1L; proteasome inhibitor experiments; in vitro methyltransferase assay with H3pT11 nucleosomes; ChIP in SESAME mutants

    PMID:32042335 PMID:36473858

    Open questions at the time
    • Whether CBP-K358ac regulatory axis operates beyond colon cancer unknown
    • Deacetylase(s) that reverse K358ac not identified
    • Integration of H3T11ph inhibition with H2Bub/H4K16ac activation at individual loci not studied

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how DOT1L achieves locus-specific methylation state outcomes (me1 vs me2 vs me3), the structural basis of its catalytic-independent role in transcription elongation, and whether the multiple allosteric inputs (H2BK120ub, H2BK34ub, H4K16ac, H3T11ph) are integrated simultaneously on single nucleosomes in vivo.
  • No structure of DOT1L engaged with multiple allosteric marks simultaneously
  • Catalytic-independent scaffolding partners and mechanism undefined
  • Therapeutic window for DOT1L inhibition across non-leukemia contexts poorly defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 8 GO:0140110 transcription regulator activity 5 GO:0042393 histone binding 4
Localization
GO:0005634 nucleus 5 GO:0005694 chromosome 3
Pathway
R-HSA-4839726 Chromatin organization 7 R-HSA-74160 Gene expression (Transcription) 7 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-73894 DNA Repair 3 R-HSA-162582 Signal Transduction 2
Partners
AF10AF9CBPCTNNB1ENLMYCNNPM1ZC3H10
Complex memberships
DotCom (DOT1L-AF9-ENL-AF10-AF17-β-catenin-Skp1-TRRAP)

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Dot1 (yeast ortholog of DOT1L) methylates lysine 79 of histone H3, which resides in the globular domain of the nucleosome core. Mutations abolishing Dot1 catalytic activity impair telomeric silencing, and dot1/H3-K79 mutations weaken the interaction of Sir2 and Sir3 with the telomeric region in vivo. Genetic mutagenesis of H3-K79 and Dot1 catalytic residues; in vivo chromatin immunoprecipitation of Sir proteins; biochemical identification of H3K79 methylation by mass spectrometry Genes & development High 12080090
2005 H2B ubiquitylation at K123 is required for the transition from monomethylation to di- and trimethylation of H3K79 by Dot1 (processive methylation), but is dispensable for monomethylation. Dot1 binding to chromatin occurs normally in the absence of H2B-K123 ubiquitylation, indicating ubiquitylation regulates enzyme processivity rather than recruitment. Chromatin immunoprecipitation; mass spectrometry of histone modifications; genetic deletion of Rad6-Bre1 pathway components Molecular cell High 16039595
2005 Dot1-dependent H3K79 methylation is required for DNA damage checkpoint activation in yeast G1 and S phase. Loss of Dot1 prevents phosphorylation of the checkpoint adaptor Rad9 and activation of the Rad53 kinase after ionizing radiation, placing Dot1/H3K79me upstream of Rad9 in the checkpoint pathway. In human cells, H3K79 methylation by DOT1L mediates recruitment of 53BP1 via its paired tudor domains to double-strand breaks. Genetic deletion/mutagenesis; kinase phosphorylation assays; chromatin immunoprecipitation; epistasis analysis Molecular and cellular biology High 15632126 16166626
2008 DOT1L is ubiquitously coupled with active transcription in mammalian cells; it preferentially occupies the proximal transcribed region of active genes correlating with H3K79 di- and trimethylation enrichment. Dot1l mutant fibroblasts lack H3K79 di- and trimethylation at all sites, establishing DOT1L as the sole enzyme responsible for these marks. H3K79 methylation levels dynamically respond to changes in gene activity. ChIP-chip tiling arrays; Dot1l mutant fibroblasts; genome-wide correlation of H3K79me with mRNA abundance Molecular and cellular biology High 18285465
2009 H2B monoubiquitination at K123 is the critical determinant for H3K79 trimethylation by Dot1 in yeast, confirmed independently of strain background or epitope-tagged proteins. Genetic deletion of H2B-K123 ubiquitination pathway; histone alanine-scanning mutants; mass spectrometry of methylation states The Journal of cell biology High 19667127
2010 DOT1L (Dot1l) is identified as part of a multisubunit DotCom complex including MLL fusion partners ENL, AF9/MLLT3, AF17/MLLT6, AF10/MLLT10, and Wnt pathway components TRRAP, Skp1, and β-catenin. The human DotCom complex trimethylates H3K79. Knockdown of Dot1 in Drosophila reduces Wingless target gene expression, and loss of H2B monoubiquitination (via Bre1 depletion) specifically reduces H3K79 trimethylation and Wingless target gene expression. Affinity purification/mass spectrometry of the complex; in vitro H3K79 trimethylation assay; Drosophila RNAi knockdown; genetic epistasis Genes & development High 20203130
2010 Mllt10/AF10 and DOT1L are identified as TCF4/β-catenin interacting partners in mouse intestinal crypts. Mllt10/AF10-Dot1l are recruited to Wnt target genes in a β-catenin-dependent manner, resulting in H3K79 methylation over their coding regions. MLLT10/AF10 and DOT1L are essential activators of Wnt target gene regulation; depletion of Mllt10 and Dot1l in apc-mutant zebrafish rescues intestinal differentiation defects. Proteomics (co-IP/MS); chromatin immunoprecipitation; shRNA knockdown + expression arrays; zebrafish morpholino; genetic epistasis with apc PLoS biology High 21103407
2011 Cardiac-specific knockout of Dot1L in mice causes dilated cardiomyopathy. Mechanistically, DOT1L regulates Dystrophin (Dmd) transcription and stability of the Dystrophin-glycoprotein complex; expression of a miniDmd rescues the cardiomyopathy phenotype, establishing Dmd as the major downstream target of DOT1L in cardiomyocytes. Conditional cardiac knockout mouse; gene expression analysis; miniDmd rescue experiment; Western blot for Dystrophin-glycoprotein complex Genes & development High 21289070
2011 Dot1 and H3K79 methylation (yeast) are required for global genomic repair (GGR) but not transcription-coupled repair (TCR) in nucleotide excision repair. Dot1/H3K79me facilitates GGR independently of checkpoint activation or regulation of Rad16 expression, suggesting methylated H3K79 serves as a docking site for the GGR machinery on chromatin. Genetic deletion of Dot1; UV-induced DNA damage repair assays in nucleosomal and linker DNA regions; epistasis with checkpoint and repair mutants The Journal of biological chemistry Medium 21460225
2012 Crystal structures of DOT1L with aminonucleoside inhibitors reveal a conformational adaptation mechanism: high-affinity inhibitor binding induces a conformational change in DOT1L that also plays a role in natural SAM substrate interactions and enzyme turnover, explaining slow dissociation kinetics. X-ray crystallography; structure-activity relationship studies; enzyme kinetics (kon/koff measurement) Chemical biology & drug design High 22978415
2013 The AF9/ENL-binding site in human DOT1L was mapped to a 10-amino acid region (DOT1L865-874). Alanine scanning mutagenesis identified four conserved hydrophobic residues essential for interaction with AF9/ENL. The AF9/ENL-interacting site is essential for immortalization by MLL-AF9, establishing that DOT1L recruitment via this interaction is required for MLL-AF9-driven transformation. Biochemical mapping (alanine scanning mutagenesis); biophysical binding assays; functional immortalization assay The Journal of biological chemistry High 23996074
2013 DOT1L crystal structure in complex with Bromo-deaza-SAH reveals that a halogen atom at the adenosine scaffold creates selective contacts with the DOT1L active site, explaining selectivity over other methyltransferases. X-ray crystallography; enzyme inhibition assays Bioorganic & medicinal chemistry High 23433670
2013 Dot1-dependent H3K79 methylation activates the meiotic checkpoint effector Mek1 kinase by promoting Hop1 activation and proper distribution along meiotic chromosomes; Dot1 is required for Mek1 autophosphorylation but not Mec1/Tel1-dependent phosphorylation. H3K79me excludes Pch2 from chromosomes, enabling Hop1 localization along chromosome axes. Genetic analysis of dot1 deletion and H3-K79 mutants; meiotic checkpoint assays; Mek1 phosphorylation assays; Hop1 and Pch2 localization by microscopy PLoS genetics High 23382701
2014 The AF9 YEATS domain binds H3K9 acetylation (and to lesser extent H3K27ac and H3K18ac). Crystal structural studies reveal an eight-stranded immunoglobulin fold with a serine-lined aromatic sandwiching cage for acetyllysine recognition. Genome-wide colocalization of AF9 and H3K9ac is important for chromatin recruitment of the H3K79 methyltransferase DOT1L, establishing a direct link between histone acetylation and DOT1L-mediated H3K79 methylation. Crystal structure of AF9 YEATS with acetyl-H3K9 peptide; ChIP-seq; mutagenesis; in vitro binding assays Cell High 25417107
2016 BRD4 and DOT1L exist in separate protein complexes in cells but show functional interdependence at MLL leukemia genes. DOT1L, via dimethylated H3K79, facilitates histone H4 acetylation, which in turn regulates BRD4 binding to chromatin. This functional collaboration is especially important at highly transcribed genes near superenhancers. Quantitative proteomics; chemoproteomics; biochemical fractionation; genetic disruption; small-molecule inhibition; ChIP Nature structural & molecular biology High 27294782
2018 Crystal structures of DOT1L-AF10 complex reveal that AF10 octapeptide motif leucine zipper (OM-LZ) directly binds the coiled-coil domain of DOT1L. Zinc stabilizes the DOT1L-AF10 complex. Disruption of the DOT1L-AF10 interface abrogates MLL-AF10-associated leukemic transformation. X-ray crystallography of apo AF10OM-LZ and DOT1L-AF10 complex; mutagenesis of interface residues; functional leukemic transformation assay Genes & development High 29563185
2019 Cryo-EM structure of DOT1L bound to a nucleosome with site-specifically ubiquitylated H2BK120 shows that DOT1L engages the nucleosome acidic patch using a variant arginine anchor and occupies a conformation poised for methylation. DOT1L and H2BK120-linked ubiquitin interact directly through complementary hydrophobic surfaces, providing the structural basis for trans-histone crosstalk activation of DOT1L. Cryo-electron microscopy (cryo-EM) structure of DOT1L-ubiquitylated nucleosome complex; site-specific ubiquitylation reconstitution Cell reports High 30759380
2019 DOT1L co-localizes with estrogen receptor α (ERα) in breast cancer cell chromatin to regulate estrogen target gene transcription. DOT1L blockade reduces H3K79 methylation and suppresses ERα and FOXA1 gene expression, providing a mechanism for DOT1L's role in breast cancer cell proliferation. ChIP-seq colocalization; siRNA knockdown; pharmacological inhibition (EPZ5676); gene expression analysis; xenograft model Science advances Medium 30775443
2020 DOT1L has a catalytic-independent role in promoting productive transcription elongation: DOT1L loss (but not catalytic inactivation) exacerbates transcription elongation defects caused by super elongation complex inhibition, establishing that DOT1L's role in elongation is distinct from its H3K79 methylation activity. DOT1L loss (but not catalytic inactivation) is also required for neural progenitor cell fate determination. DOT1L knockout vs catalytically dead DOT1L knock-in ESC models; transcriptome analysis; super elongation complex inhibitor treatment; neural progenitor differentiation assays Proceedings of the National Academy of Sciences of the United States of America High 33077595
2020 DOT1L controls CD8+ T cell differentiation by ensuring normal T cell receptor density and signaling, and maintains epigenetic identity by indirectly supporting repression of developmentally regulated genes. T cell-specific Dot1L ablation causes loss of naïve CD8+ T cells and premature differentiation toward a memory-like state in a cell-intrinsic manner. T cell-specific conditional Dot1L knockout; flow cytometry; TCR signaling assays; epigenomic and transcriptomic analysis Proceedings of the National Academy of Sciences of the United States of America High 32764145
2020 DOT1L interacts with Zc3h10 transcription factor and is recruited by Zc3h10 to promoter regions of thermogenic genes (including Ucp1) in brown adipose tissue, where it methylates H3K79 to function as a coactivator. DOT1L ablation in brown fat (Ucp1-Cre) prevents Ucp1 activation and reduces thermogenic capacity, promoting adiposity. Co-immunoprecipitation; ChIP; conditional Dot1L knockout (Ucp1-Cre); thermogenic gene expression and energy expenditure assays eLife High 33107819
2020 DOT1L inhibition in prostate cancer cells leads to reduced MYC expression and upregulation of MYC-regulated E3 ubiquitin ligases HECTD4 and MYCBP2, which promote AR and MYC protein degradation. A distal H3K79 methylation-marked enhancer in the MYC gene is bound by both AR and DOT1L in AR-positive cells. Genetic and chemical inhibition of DOT1L; ChIP; co-immunoprecipitation; ubiquitin ligase functional assays; organoids Nature communications Medium 32814769
2020 CBP mediates DOT1L K358 acetylation in colon cancer cells. This acetylation prevents RNF8 binding to DOT1L and subsequent proteasomal degradation, thereby stabilizing DOT1L without affecting its enzymatic activity. Stabilized DOT1L then catalyzes H3K79 methylation of SNAIL and ZEB1 gene promoters to promote epithelial-mesenchymal transition and metastasis. Affinity purification and mass spectrometry identifying acetylation; co-immunoprecipitation of RNF8-DOT1L; proteasome inhibitor assays; ChIP; acetylation mimic mutant; in vivo metastasis model Theranostics High 32042335
2021 H4K16 acetylation allosterically stimulates yeast Dot1 H3K79 methyltransferase activity in a manner distinct from but coordinating with H2B ubiquitination (H2BUb). H4K16ac specifically (not other H4 acetylations) and H2BUb play crucial roles in H3K79 di- and trimethylation in vitro and in vivo. In vitro reconstitution methyltransferase assay with defined histone modifications; mutagenesis; ChIP in yeast mutants Science (New York, N.Y.) High 33479126
2022 Cryo-EM structures of Dot1L bound to a H2BK34ub nucleosome reveal that H2BK34-anchored ubiquitin does not directly contact Dot1L (unlike H2BK120ub), but instead induces DNA and histone distortion around the modified site, positioning Dot1L in a productive conformation. This establishes nucleosome distortion as a distinct mechanism for ubiquitination-dependent activation of Dot1L. Cryo-EM structure of Dot1L-H2BK34ub nucleosome and H2BK34ub nucleosome alone; site-specific ubiquitylation; in vitro methyltransferase assay Nature chemical biology High 35739357
2022 H3K79me2 regulates highly specific transcriptional networks during cardiogenesis rather than acting as a general transcriptional activator. H3K79me2 in gene bodies and regulatory elements synergize to promote gene activation, and H3K79me2 at specific regulatory elements also contributes to silencing of genes not normally expressed in cardiomyocytes. DOT1L is particularly important for left ventricle-specific genes and postnatal cardiomyocyte cell cycle withdrawal. Embryonic cardiomyocyte-specific Dot1L conditional knockout; H3K79me2 ChIP-seq; RNA-seq; analysis of mononuclear cardiomyocytes Nature communications High 36460641
2022 DOT1L maintains spermatogonial stem cell self-renewal by promoting expression of fate-determining HoxC transcription factors; H3K79me2 accumulates at HoxC9 and HoxC10 gene loci. Mice lacking DOT1L fail to maintain spermatogonial stem cells, leading to progressive loss of germ cells and Sertoli cell-only syndrome. Conditional Dot1L knockout; transplantation assay; H3K79me2 ChIP; gene expression analysis Genes & development High 35738678
2022 H3T11 phosphorylation by the SESAME complex (pyruvate kinase Pyk1) directly inhibits Dot1-catalyzed H3K79 trimethylation by reducing Dot1 binding to chromatin. This crosstalk regulates autophagy gene transcription and telomere silencing; H3pT11 and H3K79me3 work together to promote SIR complex binding at telomeres. In vitro methyltransferase assay; ChIP; genetic analysis of SESAME/Pyk1 and Dot1 mutants; autophagy assays Nature communications High 36473858
2018 DOT1L facilitates nucleotide excision repair (NER) of UV-induced DNA damage by methylating H3K79, with H3K79-methylated chromatin recruiting the XPC damage recognition factor to DNA damage sites for NER. DOT1L mutations in melanoma functionally compromise methyltransferase enzyme activity leading to reduced H3K79 methylation and impaired UV-induced DNA damage repair. Functional methyltransferase assay of DOT1L mutants; ChIP of XPC at damage sites; Dot1L knockout mouse + UVR exposure; NER assays Nature communications High 29343685
2020 The lncRNA LAMP5-AS1 directly binds the lysine-rich region of the DOT1L catalytic domain and facilitates its methyltransferase activity, promoting global H3K79 dimethylation and trimethylation in MLL leukemia cells, leading to upregulated HOXA cluster gene expression. RNA electrophoretic mobility shift assay (EMSA); in vitro histone methyltransferase assay; RNA pulldown; RNA FISH; ChIP Journal of hematology & oncology Medium 32552847
2017 N-Myc upregulates DOT1L mRNA and protein by binding to the DOT1L gene promoter. DOT1L protein binds to the Myc Box II domain of N-Myc protein and knockdown of DOT1L reduces H3K79 methylation and N-Myc binding at target gene promoters, establishing DOT1L as a cofactor in N-Myc-mediated transcriptional activation. ChIP at DOT1L promoter; co-immunoprecipitation of DOT1L-N-Myc; shRNA knockdown; ChIP at target promoters; xenograft model Cancer research Medium 28209620
2010 The DOT1L-containing complex purified by tandem affinity purification contains AF9, ENL, and NPM1 as major interacting proteins. The network suggests DOT1L controls AF9- and ENL-mediated transcription and may function as a histone chaperone in an NPM1-dependent manner. Tandem affinity purification; mass spectrometry The protein journal Medium 20431927
2021 DOT1L controls B cell differentiation by promoting a pro-proliferative, pro-germinal center (GC) transcriptional program and indirectly supporting repression of PRC2 targets (plasma cell differentiation program). B cells lacking Dot1L fail to establish germinal centers and show premature acquisition of plasma cell characteristics. Conditional Dot1L knockout in B cells; flow cytometry; combined epigenomics and transcriptomics; in vitro and in vivo differentiation assays EMBO reports High 33410591
2022 DOT1L is required for transcription of major satellite repeats at pericentromeric heterochromatin in mouse ESCs and cleavage-stage embryos. H3K79me3 is selectively enriched over H3K79me2 at repetitive elements; DOT1L loss compromises pericentromeric satellite transcription and destabilizes heterochromatin structures, with possible coordination between DOT1L and chromatin remodeler SMARCA5. ChIP-seq distinguishing H3K79me2 and me3; DOT1L knockout in mESCs; pericentromeric transcript quantification; heterochromatin stability assays; preimplantation viability assay EMBO reports High 37317657
2021 DOT1L promotes expression of Spleen tyrosine kinase (SYK) by increasing H3K79me2 modification at the SYK promoter in cardiac fibroblasts; this activates TGF-β1/Smad3 signaling to drive cardiac fibrosis. Inhibition of DOT1L reduces SYK transcription and ameliorates cardiac fibrosis in vitro and in vivo. ChIP-qPCR for H3K79me2 at SYK promoter; DOT1L knockdown/inhibition; SYK overexpression rescue; mouse myocardial infarction model Human cell Medium 34635982
2022 DOT1L directly regulates macrophage lipid biosynthesis gene programs including SREBP1 and SREBP2. In myeloid-specific Dot1l-deficient mice, atherosclerotic plaque stability is reduced and inflammatory plaque macrophages are hyperactivated, establishing a role for DOT1L-mediated H3K79 methylation in macrophage lipid regulation. Selective DOT1L inhibitor in mouse and human macrophages; myeloid-specific Dot1l conditional knockout; RNA-seq; in vivo atherosclerosis model Cell reports High 36417856
2017 DOT1L in Xenopus functions as a coactivator for thyroid hormone receptor (TR). Overexpression of Dot1L enhances gene activation by TR in the presence of T3; endogenous Dot1L is critical for T3-induced activation of endogenous TR target genes in premetamorphic tadpoles, and transgenic Dot1L enhances TR function in vivo. Cotransfection studies; reconstituted frog oocyte in vivo transcription system; X. laevis transgenesis; X. tropicalis gene knockdown FASEB journal Medium 28739643
2018 MLL1 and DOT1L cooperate to maintain expression of the Hoxa9/Meis1 gene expression program required for MN1-driven AML; deletion of either Mll1 or Dot1l abrogates this cell-of-origin gene expression program and blocks leukemogenesis. MN1hi/HOXA9hi human leukemias are sensitive to pharmacological DOT1L inhibition. Genetic inactivation of Dot1l or Mll1 in MN1-expressing cells; gene expression arrays; pharmacological DOT1L inhibition in human leukemia cells The Journal of clinical investigation High 26927674

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood 596 23801631
2011 The diverse functions of Dot1 and H3K79 methylation. Genes & development 464 21724828
2002 Lysine methylation within the globular domain of histone H3 by Dot1 is important for telomeric silencing and Sir protein association. Genes & development 429 12080090
2008 DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells. Molecular and cellular biology 397 18285465
2014 AF9 YEATS domain links histone acetylation to DOT1L-mediated H3K79 methylation. Cell 318 25417107
2010 Linking H3K79 trimethylation to Wnt signaling through a novel Dot1-containing complex (DotCom). Genes & development 260 20203130
2005 The DNA damage checkpoint response requires histone H2B ubiquitination by Rad6-Bre1 and H3 methylation by Dot1. The Journal of biological chemistry 242 15632126
2005 Role of Dot1-dependent histone H3 methylation in G1 and S phase DNA damage checkpoint functions of Rad9. Molecular and cellular biology 240 16166626
2005 Histone H2B ubiquitylation controls processive methylation but not monomethylation by Dot1 and Set1. Molecular cell 198 16039595
2011 Requirement for Dot1l in murine postnatal hematopoiesis and leukemogenesis by MLL translocation. Blood 171 21398221
2018 DOT1L and H3K79 Methylation in Transcription and Genomic Stability. Biomolecules 165 29495487
2000 Role for the silencing protein Dot1 in meiotic checkpoint control. Molecular biology of the cell 139 11029058
2010 Histone H3 lysine 79 methyltransferase Dot1 is required for immortalization by MLL oncogenes. Cancer research 138 21159644
2011 DOT1L regulates dystrophin expression and is critical for cardiac function. Genes & development 121 21289070
2006 Selective di- or trimethylation of histone H3 lysine 76 by two DOT1 homologs is important for cell cycle regulation in Trypanosoma brucei. Molecular cell 120 16916638
2017 DOT1L safeguards cartilage homeostasis and protects against osteoarthritis. Nature communications 118 28627522
2010 Early mammalian erythropoiesis requires the Dot1L methyltransferase. Blood 115 20798234
2019 Structural Basis for Recognition of Ubiquitylated Nucleosome by Dot1L Methyltransferase. Cell reports 111 30759380
2012 Conformational adaptation drives potent, selective and durable inhibition of the human protein methyltransferase DOT1L. Chemical biology & drug design 109 22978415
2009 Histone H2BK123 monoubiquitination is the critical determinant for H3K4 and H3K79 trimethylation by COMPASS and Dot1. The Journal of cell biology 107 19667127
2014 The emerging roles of DOT1L in leukemia and normal development. Leukemia 102 24854991
2016 Complementary activities of DOT1L and Menin inhibitors in MLL-rearranged leukemia. Leukemia 96 27840424
2014 The histone methyltransferase Dot1/DOT1L as a critical regulator of the cell cycle. Cell cycle (Georgetown, Tex.) 95 24526115
2016 Functional interdependence of BRD4 and DOT1L in MLL leukemia. Nature structural & molecular biology 92 27294782
2011 Dot1 and histone H3K79 methylation in natural telomeric and HM silencing. Molecular cell 92 21474073
2020 Histone methyltransferase DOT1L coordinates AR and MYC stability in prostate cancer. Nature communications 89 32814769
2016 The upstreams and downstreams of H3K79 methylation by DOT1L. Chromosoma 88 26728620
2021 Regulation of the Dot1 histone H3K79 methyltransferase by histone H4K16 acetylation. Science (New York, N.Y.) 86 33479126
2019 Inhibition of histone methyltransferase DOT1L silences ERα gene and blocks proliferation of antiestrogen-resistant breast cancer cells. Science advances 82 30775443
2022 H2B Lys34 Ubiquitination Induces Nucleosome Distortion to Stimulate Dot1L Activity. Nature chemical biology 79 35739357
2010 The leukemia-associated Mllt10/Af10-Dot1l are Tcf4/β-catenin coactivators essential for intestinal homeostasis. PLoS biology 75 21103407
2013 A medicinal chemistry perspective for targeting histone H3 lysine-79 methyltransferase DOT1L. Journal of medicinal chemistry 68 23879463
2009 ES cell cycle progression and differentiation require the action of the histone methyltransferase Dot1L. Stem cells (Dayton, Ohio) 66 19544450
2017 The Histone Methyltransferase DOT1L Promotes Neuroblastoma by Regulating Gene Transcription. Cancer research 62 28209620
2022 DOT1L Is a Novel Cancer Stem Cell Target for Triple-Negative Breast Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 60 35135840
2020 The lncRNA LAMP5-AS1 drives leukemia cell stemness by directly modulating DOT1L methyltransferase activity in MLL leukemia. Journal of hematology & oncology 60 32552847
2018 The protective role of DOT1L in UV-induced melanomagenesis. Nature communications 60 29343685
2019 DOT1L: a key target in normal chromatin remodelling and in mixed-lineage leukaemia treatment. Epigenetics 59 31790636
2017 Cooperative gene activation by AF4 and DOT1L drives MLL-rearranged leukemia. The Journal of clinical investigation 58 28394257
2020 DOT1L-controlled cell-fate determination and transcription elongation are independent of H3K79 methylation. Proceedings of the National Academy of Sciences of the United States of America 57 33077595
2022 Targeting the histone H3 lysine 79 methyltransferase DOT1L in MLL-rearranged leukemias. Journal of hematology & oncology 54 35331314
2015 Mixed lineage rearranged leukaemia: pathogenesis and targeting DOT1L. Current opinion in hematology 53 25635757
2013 Dot1-dependent histone H3K79 methylation promotes activation of the Mek1 meiotic checkpoint effector kinase by regulating the Hop1 adaptor. PLoS genetics 52 23382701
2013 Bromo-deaza-SAH: a potent and selective DOT1L inhibitor. Bioorganic & medicinal chemistry 52 23433670
2016 Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach. ACS medicinal chemistry letters 51 27563395
2011 Evidence that the histone methyltransferase Dot1 mediates global genomic repair by methylating histone H3 on lysine 79. The Journal of biological chemistry 51 21460225
2018 The histone methyltransferase DOT1L inhibits osteoclastogenesis and protects against osteoporosis. Cell death & disease 49 29348610
2010 Characterization of the DOT1L network: implications of diverse roles for DOT1L. The protein journal 49 20431927
2019 DOT1L promotes progenitor proliferation and primes neuronal layer identity in the developing cerebral cortex. Nucleic acids research 46 30329130
2009 The Dot1 histone methyltransferase and the Rad9 checkpoint adaptor contribute to cohesin-dependent double-strand break repair by sister chromatid recombination in Saccharomyces cerevisiae. Genetics 46 19332880
2020 CBP mediated DOT1L acetylation confers DOT1L stability and promotes cancer metastasis. Theranostics 44 32042335
2019 miR-133b suppresses colorectal cancer cell stemness and chemoresistance by targeting methyltransferase DOT1L. Experimental cell research 43 31525340
2008 Role of Dot1 in the response to alkylating DNA damage in Saccharomyces cerevisiae: regulation of DNA damage tolerance by the error-prone polymerases Polzeta/Rev1. Genetics 42 18562671
2018 Methyltransferase Dot1l preferentially promotes innate IL-6 and IFN-β production by mediating H3K79me2/3 methylation in macrophages. Cellular & molecular immunology 41 30275539
2020 The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8+ T cells. Proceedings of the National Academy of Sciences of the United States of America 40 32764145
2017 Discovery of Potent, Selective, and Structurally Novel Dot1L Inhibitors by a Fragment Linking Approach. ACS medicinal chemistry letters 40 28337327
2022 Histone Methyltransferase DOT1L as a Promising Epigenetic Target for Treatment of Solid Tumors. Frontiers in genetics 38 35495127
2015 DOT1L Activity Promotes Proliferation and Protects Cortical Neural Stem Cells from Activation of ATF4-DDIT3-Mediated ER Stress In Vitro. Stem cells (Dayton, Ohio) 38 26299268
2021 Histone methyltransferase DOT1L controls state-specific identity during B cell differentiation. EMBO reports 37 33410591
2013 Targeting recruitment of disruptor of telomeric silencing 1-like (DOT1L): characterizing the interactions between DOT1L and mixed lineage leukemia (MLL) fusion proteins. The Journal of biological chemistry 37 23996074
2021 Hesperetin promotes DOT1L degradation and reduces histone H3K79 methylation to inhibit gastric cancer metastasis. Phytomedicine : international journal of phytotherapy and phytopharmacology 36 33667841
2020 The Histone Methyltransferase DOT1L Is Essential for Humoral Immune Responses. Cell reports 36 33326791
2016 MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemia. The Journal of clinical investigation 35 26927674
2018 Increased susceptibility to develop spontaneous and post-traumatic osteoarthritis in Dot1l-deficient mice. Osteoarthritis and cartilage 34 30513362
2020 The Methyltransferase DOT1L Controls Activation and Lineage Integrity in CD4+ T Cells during Infection and Inflammation. Cell reports 33 33326781
2018 DOT1L inhibition blocks multiple myeloma cell proliferation by suppressing IRF4-MYC signaling. Haematologica 33 30171029
2022 The histone methyltransferase DOT1L is a new epigenetic regulator of pulmonary fibrosis. Cell death & disease 31 35039472
2019 Inhibition of DOT1L and PRMT5 promote synergistic anti-tumor activity in a human MLL leukemia model induced by CRISPR/Cas9. Oncogene 31 31417187
2010 Regulation of tolerance to DNA alkylating damage by Dot1 and Rad53 in Saccharomyces cerevisiae. DNA repair 31 20674515
2019 New Potent DOT1L Inhibitors for in Vivo Evaluation in Mouse. ACS medicinal chemistry letters 30 31857842
2022 Histone methyltransferase DOT1L is essential for self-renewal of germline stem cells. Genes & development 29 35738678
2022 DOT1L regulates lipid biosynthesis and inflammatory responses in macrophages and promotes atherosclerotic plaque stability. Cell reports 29 36417856
2019 The miR-216a-Dot1l Regulatory Axis Is Necessary and Sufficient for Müller Glia Reprogramming during Retina Regeneration. Cell reports 28 31433981
2011 Dot1 binding induces chromatin rearrangements by histone methylation-dependent and -independent mechanisms. Epigenetics & chromatin 28 21291527
2021 Hypoxia induces DOT1L in articular cartilage to protect against osteoarthritis. JCI insight 27 34727094
2013 DOT1L-mediated H3K79 methylation in chromatin is dispensable for Wnt pathway-specific and other intestinal epithelial functions. Molecular and cellular biology 27 23428873
2018 Differential Methylation of H3K79 Reveals DOT1L Target Genes and Function in the Cerebellum In Vivo. Molecular neurobiology 25 30302725
2022 DOT1L regulates chamber-specific transcriptional networks during cardiogenesis and mediates postnatal cell cycle withdrawal. Nature communications 23 36460641
2017 The Putative Histone Methyltransferase DOT1 Regulates Aflatoxin and Pathogenicity Attributes in Aspergillus flavus. Toxins 23 28737735
2018 Structural and functional analysis of the DOT1L-AF10 complex reveals mechanistic insights into MLL-AF10-associated leukemogenesis. Genes & development 21 29563185
2022 Combinatorial targeting of a chromatin complex comprising Dot1L, menin and the tyrosine kinase BAZ1B reveals a new therapeutic vulnerability of endocrine therapy-resistant breast cancer. Breast cancer research : BCR 19 35850772
2018 Transcriptional activator DOT1L putatively regulates human embryonic stem cell differentiation into the cardiac lineage. Stem cell research & therapy 19 29631608
2024 Distinct Responses to Menin Inhibition and Synergy with DOT1L Inhibition in KMT2A-Rearranged Acute Lymphoblastic and Myeloid Leukemia. International journal of molecular sciences 18 38892207
2020 Epigenetic priming by Dot1l in lymphatic endothelial progenitors ensures normal lymphatic development and function. Cell death & disease 18 31908356
2022 The Role of DOT1L in Normal and Malignant Hematopoiesis. Frontiers in cell and developmental biology 17 35712672
2021 Histone Methyltransferase Dot1L Contributes to RIPK1 Kinase-Dependent Apoptosis in Cerebral Ischemia/Reperfusion. Journal of the American Heart Association 17 34796721
2022 SESAME-catalyzed H3T11 phosphorylation inhibits Dot1-catalyzed H3K79me3 to regulate autophagy and telomere silencing. Nature communications 16 36473858
2021 Epigenome-Wide Association Study of Thyroid Function Traits Identifies Novel Associations of fT3 With KLF9 and DOT1L. The Journal of clinical endocrinology and metabolism 16 33484127
2021 Elucidating the Importance of DOT1L Recruitment in MLL-AF9 Leukemia and Hematopoiesis. Cancers 16 33562706
2020 Targeted disruption of the histone lysine 79 methyltransferase Dot1L in nephron progenitors causes congenital renal dysplasia. Epigenetics 16 33315499
2023 DOT1L bridges transcription and heterochromatin formation at mammalian pericentromeres. EMBO reports 15 37317657
2022 Inhibition of the cardiac fibroblast-enriched histone methyltransferase Dot1L prevents cardiac fibrosis and cardiac dysfunction. Cell & bioscience 15 35986422
2022 Combinatorial targeting of menin and the histone methyltransferase DOT1L as a novel therapeutic strategy for treatment of chemotherapy-resistant ovarian cancer. Cancer cell international 15 36333801
2021 Role of Dot1L and H3K79 methylation in regulating somatic hypermutation of immunoglobulin genes. Proceedings of the National Academy of Sciences of the United States of America 15 34253616
2021 Histone methyltransferase DOT1L mediates the TGF-β1/Smad3 signaling pathway through epigenetic modification of SYK in myocardial infarction. Human cell 15 34635982
2020 Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes. eLife 15 33107819
2019 The Role of Dot1l in Prenatal and Postnatal Murine Chondrocytes and Trabecular Bone. JBMR plus 15 32083237
2017 DOT1L inhibitor improves early development of porcine somatic cell nuclear transfer embryos. PloS one 15 28632762
2017 Histone methyltransferase Dot1L is a coactivator for thyroid hormone receptor during Xenopus development. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 15 28739643
2020 Nullifying epigenetic writer DOT1L attenuates neointimal hyperplasia. Atherosclerosis 14 32799103