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Symbol DOT1L contributors: mct/pgu - updated : 07-05-2015
HGNC name DOT1-like, histone H3 methyltransferase (S. cerevisiae)
HGNC id 24948
Location 19p13.3      Physical location : 2.164.147 - 2.232.576
Synonym name
  • histone-lysine N-methyltransferase
  • H3 lysine-79 specific
  • disruptor of Telomere Silencing 1-Like
  • histone methyltransferase DOT1L
  • H3-K79-HMTase
  • Synonym symbol(s) DOT1, KIAA1814, KMT4, DKFZp586P1823
    TYPE functioning gene
    STRUCTURE 68.43 kb     28 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    Physical map
    MBD3 19p13.3 methyl-CpG binding domain protein 3 UQCR 19p13.3 ubiquinol-cytochrome c reductase (6.4kD) subunit TCF3 19p13.3 transcription factor 3 (E2A immunoglobulin enhancer binding factors E12/E47) LOC126435 19p13.3 hypothetical LOC126435 LOC390874 19 similar to onecut 3 ATP8B3 19p13.3 ATPase, Class I, type 8B, member 3 EloA-BP1 KLF16 19p13.3 Kruppel-like factor 16 MGC5244 19p13.3 hypothetical protein MGC5244 SCAMP-4 19p13.3 secretory carrier membrane protein 4 LOC113179 19p13.3 hypothetical protein BC011824 MGC39696 19p13.3 hypothetical protein MGC39696 CSNK1G2 19p13.3 casein kinase 1, gamma 2 BTBD2 19p13.3 BTB (POZ) domain containing 2 MKNK2 19p13.3 MAP kinase-interacting serine/threonine kinase 2 moblak IMAGE:4215339 19p13.3 hypothetical protein IMAGE:4215339 AP3D1 19p13.3 adaptor-related protein complex 3, delta 1 subunit DOT1L 19p13.3 adaptor-related protein complex 3, delta 1 subunit SF3A2 19p13.3 splicing factor 3a, subunit 2, 66kDa GNRPX 19p13.3 likely ortholog of mouse guanine nucleotide releasing protein x AMH 19p13.3 anti-Mullerian hormone FLJ32416 19p13.3 homolog of mouse skeletal muscle sarcoplasmic reticulum protein JP-45 OAZ1 19p13.3 ornithine decarboxylase antizyme 1 FLJ45778 19p13.3 FLJ45778 protein LOC388489 19 hypothetical gene supported by AK091795 LSM7 19p13.3 LSM7 homolog, U6 small nuclear RNA associated (S. cerevisiae) SPPL2B 19p13.3 LSM7 homolog, U6 small nuclear RNA associated (S. cerevisiae) LOC360200  polyserase 1 TIMM13 19p13.3 translocase of inner mitochondrial membrane 13 homolog (yeast) LMNB2 19p13.3 lamin B2 GADD45B 19p13.3 growth arrest and DNA-damage-inducible, beta FLJ00058 19p13.3 hypothetical protein FLJ00058 GNG7 19p13.3 guanine nucleotide binding protein (G protein), gamma 7 LOC390875 19 similar to fos39347_1 DIRAS1 19p13.3 DIRAS family, GTP-binding RAS-like 1 LOC388490 19 LOC388490 SLC39A3 19p13.3 solute carrier family 39 (zinc transporter), member 3
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    28 - 7455 - 1537 - 2003 12628190
    Type widely
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestinesmall intestine  moderately
    Lymphoid/Immunelymph node   predominantly
     spleen   highly
    Reproductivemale systemtestis  highly
    Respiratorylung   moderately
    SystemCellPubmedSpeciesStageRna symbol
    Respiratoryalveolar macrophage
    cell lineage
    cell lines
    fluid/secretion blood
    at STAGE
    physiological period fetal
    Text liver, brain
  • a lysine-rich DNA binding domain in the N-terminal region, which binds to ubiquitin
  • a C-terminal domain having similarities to SAM motif for protein-protein interaction (catalytic domain), interacting with a stretch of basic AAs in the histone H4 tail, and a lysine-rich region in the catalytic domain, potentially crucial for direct interaction with H2B ubiquitylation and high level methylation of H3K79
    interspecies homolog to yeast Dot1
    ortholog to murine Dot1l
  • DOT1 family
  • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     intracellular
  • binds to the nucleosome, recognizes the H4 basic tail and begins to methylate H3K79 (monomethylation)
  • basic FUNCTION
  • playing a role in nucleosomal histone methylation
  • methylating Lys-79 of histone H3
  • recruitment important for transformation by the MLL-MLLT1 fusion derivative
  • can promote an oncogenic pattern of gene expression through binding with several MLL fusion partners found in acute leukemia
  • through H3K79 methylation play important roles in heterochromatin formation and in embryonic development
  • a unique histone methyltransferase that specifically methylates histone H3 at lysine 79
  • DOT1L-dependent H3K79 methylation serves as a critical regulator of a differentiation switch during early hematopoiesis
  • involved in the regulation of telomeric silencing, development, cell cycle checkpoint and transcription
  • might control AF9- and ENL-mediated transcription, regulate RNA processing, and function as a histone chaperone in a NPM1-dependent manner
  • responsible for methylation of histone H3 at lysine 79 and is involved in the pathobiology of several leukemias, the majority of which are characterized by chromosomal translocations involving the mixed lineage leukemia (MLL) gene
  • may contribute to euchromatin formation or transcription
  • DOT1L-dependent lysine 79 of histone H3 methylation serves potentially as a critical regulator of a differentiation switch during early hematopoiesis
  • critical role for DOT1L-mediated H3K79 methylation in cardiomyocyte function
  • MLLT10/AF10 and DOT1L are essential activators to a large extent dedicated to Wnt target gene regulation
  • H3K79 methyltransferase, required for both initiation and maintenance of MLL-AF9-induced leukemogenesis
  • DOT1L participates in the regulation of transcription, development, erythropoiesis, differentiation, and proliferation of normal cells
  • DOT1L promotes the formation of the pre-initiation complex on the promoters of UV-repressed genes and the appearance of transcriptionally active chromatin marks
  • is involved in a number of key processes ranging from gene expression to DNA-damage response and cell cycle progression
  • combination of SIRT1 activators and DOT1L inhibitors shows enhanced antiproliferative activity against KMT2A-rearranged leukemia cells
    a component
    small molecule
  • MLLT10
  • DMD is a major target mediating DOT1L function in cardiomyocytes
  • multiple lineage leukemia gene (KMT2A) and DOT1L associations with the IgH gene were also impaired in the absence of ELL2
  • STAT1-DOT1L interaction is required for the regulation JAK-STAT-inducible gene expression
  • functional interaction between DOT1L and RNAPII targets DOT1L and subsequent H3K79 methylations to actively transcribed genes
  • RNF20 is a key requirement for KMT2A-fusion leukemia through regulatory cross talk with DOT1L
  • direct interaction between MLLT3/MLLT1 and DOT1L and for optimal interaction an intact C-terminal domain in KMT2A fusion proteins is critical
  • cell & other
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --low  
    in idiopathic DCM (dilated cardiomyopathy) patient samples compared with normal controls
    constitutional       loss of function
    DOT1L-deficient cells also showed abnormal mitotic spindle formation and centrosome number, suggesting that DOT1L deficiency leads to chromosomal missegregation
    Variant & Polymorphism
    Candidate gene may provide a potential target for therapeutic intervention in MLL-AF10-mediated leukemogenesis
    Therapy target
    may serve as a potential therapeutic target for the treatment of leukemia caused by MLL translocations
    may present an attractive candidate for drug targeting in colorectal cancer.
    disruption of interaction between DOT1L and MLLT3/MLLT1 is a promising therapeutic strategy with potentially fewer adverse effects than enzymatic inhibition of DOT1L for KMT2A fusion protein-associated leukemia