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FLASH GENE

Symbol

DOT1L

contributors: mct/pgu - updated : 21-11-2023

HGNC name	DOT1-like, histone H3 methyltransferase (S. cerevisiae)
HGNC id	24948

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_032482 28 - 7455 NP_115871 - 1537 - 2023 36674903 NM_001411141 28 - 9700 NP_001398070 - 1738 - 2023 36674903

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive intestine small intestine     moderately Lymphoid/Immune lymph node       predominantly   spleen       highly Reproductive male system testis     highly Respiratory lung       moderately

cells

System Cell Pubmed Species Stage Rna symbol Nervous glia Homo sapiens Nervous neuron Homo sapiens Respiratory alveolar macrophage

cell lineage
cell lines
fluid/secretion	blood

at STAGE

physiological period

fetal

Text	liver, brain

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a lysine-rich DNA binding domain in the N-terminal region, which binds to ubiquitin , and N-terminal Dot1 catalytic domain
	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

HOMOLOGY

interspecies	homolog to yeast Dot1
	ortholog to murine Dot1l
	ortholog to drosophila Grappa

Homologene

FAMILY

DOT1 family

CATEGORY

enzyme

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm
	intracellular,nucleus,nucleoplasm
text	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
	DOT1L secures likely an open chromatin structure in order to reactivate RNA Pol II transcription initiation after a genotoxic attack
	is involved in a number of key processes ranging from gene expression to DNA-damage response and cell cycle progression
	essential role for DOT1L in generating an effective humoral immune response
	combination of SIRT1 activators and DOT1L inhibitors shows enhanced antiproliferative activity against KMT2A-rearranged leukemia cells
	promotes progenitor proliferation and primes neuronal layer identity in the developing cerebral cortex
	role for the histone H3K79 methyltransferase DOT1L in controlling B-cell differentiation
	DOT1L is a key modulator of the core transcriptional and epigenetic landscape in B cells, establishing an epigenetic barrier that warrants B-cell naivety and GC B-cell differentiation
	DOT1L is an epigenetic regulator of the senescence-associated secretory phenotype (SASP), whose expression is uncoupled from the senescence-associated cell cycle arrest
	DOT1L protects against osteoarthritis, and DOT1L-mediated H3K79 methylation is reduced in human osteoarthritic joints
	is the sole H3K79 methyltransferase, and required for spermatogonial stem cell self-renewal
	essential function for DOT1L in adult stem cells and likely involved regulation of spermatogonial stem cells
	has a specialized role in transcription of major satellite repeats to maintain pericentromeric heterochromatin and genome stability
	important role for DOT1L as a bridge between transcriptional activation of repeat elements and heterochromatin stability
	methylates a lysine residue (K79) in the core globular domain of histone H3
	is a conserved H3K79 methyltransferase
	DOT1L acts in a distributive manner such that it can only sequentially add methyl groups to each H3K79 residue

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

INTERACTION

DNA

RNA

small molecule

protein	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

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

DDFHID

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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 constitutional     --low   in osteoarthritic joints

Susceptibility

Variant & Polymorphism

Candidate gene	may provide a potential target for therapeutic intervention in MLL-AF10-mediated leukemogenesis
Marker
Therapy target
	System Type Disorder Pubmed cancer hemopathy   may serve as a potential therapeutic target for the treatment of leukemia caused by MLL translocations cancer digestive colon may present an attractive candidate for drug targeting in colorectal cancer. cancer hemopathy   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 osteoarticular     local treatment with a selective hypoxia mimetic in the joint restores DOT1L function and could be an attractive therapeutic strategy for osteoarthritis cancer hemopathy   is also an important drug target for treatment of mixed lineage leukemia (MLL)-rearranged leukemia where aberrant transcriptional activation is promoted by DOT1L mislocalisation

ANIMAL & CELL MODELS

mouse germline Dot1L deletion causes embryonic lethality and defects in heart and yolk sac