DOT1L (DOT1 like histone H3K79 methyltransferase)

2016-08-01   Kathrin M. Bernt , Tobias Neff 

Pediatric Hematology\\\/Oncology\\\/BMT, University of Colorado, Aurora, CO, USA; Kathrin.Bernt@ucdenver.edu; Tobias.Neff@ucdenver.edu

Identity

HGNC
LOCATION
19p13.3. GRCh38.p7 NC_000019.10 (2163963..2232578)
IMAGE
Atlas Image
LEGEND
Gene neighbours of DOT1L on chromosome 19p13.3 (NCBI Homo sapiens Annotation Release 108).
LOCUSID
ALIAS
DOT1,KMT4

Abstract

DOT1L is a histone lysine methyltransferase (KMT). It is the only known methyltransferase for lysine residue 79 on histone 3 (H3K79). The active site of DOT1L bears more homology to the active site in Protein Arginin Methyl Transferases (PRMTs) than the SET domain of other KMTs. DOT1L has important roles in normal development and cellular differentiation. DOT1L plays especially important roles in normal hematopoiesis and in leukemia. Initially characterized as a therapeutic target in MLL-rearranged acute leukemias, recent data suggest that DOT1L is also therapeutic target in other molecular subtypes of acute leukemia and in selected solid tumors. A phase 1 clinical trial of a small molecule inhibitor of Dot1L has been described, with encouraging responses being reported.

DNA/RNA

Description

Orientation: Plus strand; 68615 bases; Exon count: 30 (NCBI Homo sapiens Annotation Release 108).

Transcription

7 transcripts for DOT1L are described in the NCBI Nucleotide database. They are predicted by computational analysis. To the best of our knowledge, the functional significance of the different transcripts is to this point unknown. In the mouse, five isoforms have been described (Zhang, W. et al., 2004).

Proteins

Atlas Image
Selected methyl residues on the N-terminal tail of histone 3 modified by histone methyltransferases. A non-comprehensive list of corresponding methyl-transferases is shown. Some methyltransferases can methylate different residues. Notable points regarding DOT1L are: 1.) DOT1L does not methylate free peptides, or free histone 3 but only whole nucleosomes. 2.) K79 is located in the nucleosome core, not the N-terminal tail. 3.) The catalytic domain is homologous to arginine methyl-transferases and does not contain a SET-domain typical for most lysine methyl-transferases.

Description

DOT1L includes several domains: catalytic domain (1-332), Bat3-interacting domain (361-380), K-rich patch (390-407) with a partially overlapping NLS (395-417), leucine zipper motif (576-594), CTD binding patch (618-627), three ENL/AF9 binding sites (628-653, 863-878, 877-900), and two more NLSs (1088-1111, 1164-1171) - reviewed in (Vlaming et al., 2016).

Localisation

DOT1L is thought to predominantly or entirely localize to the nucleus.

Function

DOT1L is the human ortholog of the yeast (S. cerevisiae) gene Disruptor of telomere silencing 1 (Dot1). The gene was reported to be involved in the regulation of telomeric gene silencing and position effect variegation (Singer et al., 1998). Interestingly, more recent data suggest that only select telomeric gene loci are regulated by Dot1 and that H3K79 methylation by Dot1 does not play a role in the maintenance of natural HML silencing but only silences the HM locus in the context of a reporter strain (Takahashi et al., 2011).
The biochemical function of yeast DOT1 and mammalian DOT1L is the methylation of the histone 3 core lysine 79 residue (Feng et al., 2002; Lacoste et al., 2002; Ng et al., 2002; van Leeuwen et al., 2002). DOT1 and hDOT1L methylate nucleosomal substrates, but not free histone H3. They have homology with arginine methyltransferases, but do not contain a SET-domain typical of most lysine methyl-transferases.
Lysine K79me2/3 is thought to be associated with expressed genes. Some evidence suggests antagonism between K79me2/3 and histone 3 lysine 9 methylation-mediated gene silencing mediated by SIRT1 and SUV39H1, which is compatible with prior findings in yeast (Ehrentraut et al., 2011). H3K79 methylation is thought to be linked to cell cycle regulation (Schulze et al., 2009) and to the DNA damage response (Giannattasio et al., 2005).
In bone marrow and leukemia, DOT1L is thought to be important in the regulation of, among other genes, the late HOXA cluster (Bernt et al., 2011; Riedel et al., 2016). In prostate cancer there is evidence for a link between androgen receptor signaling and DOT1L (Yang et al., 2013).

Homology

Homolog genes exist in Euteleostomi, with AA and DNA identity of approximately 65 - 99 % (see https://www.ncbi.nlm.nih.gov/homologene/; HomoloGene:32779). Related genes with K79 methyltransferase activity in lower species include the originally discovered yeast (S. cerevisiae) gene Dot1 (Disruptor of telomer silencing 1) (Lacoste et al., 2002; Singer et al., 1998) and the Drosophila ortholog grappa (gpp) (Shanower et al., 2005), mutants of which interestingly exhibit Pc-G phenotypes, but also display phenotypes characteristic of trithorax-group mutants.

Mutations

Note

Generally speaking, somatic and germline mutations of DOT1L have been identified, but their significance is currently unknown. One published report has suggested a link between Dot1l-mutation and Gastric Cancer (Donner et al., 2015).

Germinal

A number of germline mutations (missense and loss-of-function) are described in the Exac database (http://exac.broadinstitute.org/gene/ENSG00000104885) . The functional significance is unknown. To the best of our knowledge, there is as yet no human phenotype or syndrome associated with germline DOT1L-mutation.

Somatic

DOT1L is mutated in a number of human cancers including hematopoietic and solid tumors. The frequency of mutations is typically

Implicated in

Top note
An initial suggestion that DOT1L may have a role in cancer came from the work of Yi Zhang and his group (Okada et al., 2005). His work suggested, that DOT1L is a critical component in leukemia driven by MLL-fusions (i.e. carrying a rearrangement of the KMT2A (MLL)-gene on chromosome band 11q23).
Subsequent work has confirmed this concept, and has suggested additional cancers that might potentially be therapeutically targeted by inhibiting DOT1L. A growing number of small molecule inhibitors of DOT1L have been reported (Chen, S. et al., 2016; Luo et al., 2016; Spurr et al., 2016; Yao et al., 2011; Yi et al., 2015; Yu et al., 2013). Most of them are at the stage of a chemical probe, but the first compound to be reported (Daigle et al., 2013; Daigle et al., 2011) has shown encouraging evidence of efficacy in a Phase 1 clinical trial.
Entity name
Note
DOT1L is thought to be a therapeutic target in MLL-rearranged AML with nuclear and cytoplasmic fusion partners (Bernt et al., 2011; Deshpande et al., 2013). DOT1L is thought to be a therapeutic target in t(10;11)(p13;q14-21) PICALM (CALM) / MLLT10 (AF10) leukemia (Chen, L. et al., 2012). DOT1L has also be reported to be a therapeutic target in AML with high expression of MN1 (Riedel et al., 2016), AML with IDH-mutations (Sarkaria et al., 2014), AML with DNMT3A mutations (Lu et al., 2016; Rau et al., 2016) and AML with NPM1 mutations (Kuhn et al., 2016).
Entity name
Prostate Cancer
Note
DOT1L has been linked to the regulation of androgen receptor regulated gene activation programs in prostate cancer (Yang et al., 2013). A fusion gene DOT1L/ HES6 has been described in prostate cancer (Annala et al., 2014). Of note, this fusion reportedly drives androgen independent growth of prostate cancer.
Entity name
Breast Cancer
Note
DOT1L has been suggested as a therapeutic target in breast cancer (Zhang, L. et al., 2014).

Bibliography

Pubmed IDLast YearTitleAuthors
250061832014DOT1L-HES6 fusion drives androgen independent growth in prostate cancer.Annala M et al
217415972011MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L.Bernt KM et al
231381832013Abrogation of MLL-AF10 and CALM-AF10-mediated transformation through genetic inactivation or pharmacological inhibition of the H3K79 methyltransferase Dot1l.Chen L et al
269148522016Identification of Novel Disruptor of Telomeric Silencing 1-like (DOT1L) Inhibitors through Structure-Based Virtual Screening and Biological Assays.Chen S et al
217415962011Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor.Daigle SR et al
233619072013Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l.Deshpande AJ et al
255762412015Exome sequencing reveals three novel candidate predisposition genes for diffuse gastric cancer.Donner I et al
218966562011Structural basis for the role of the Sir3 AAA+ domain in silencing: interaction with Sir4 and unmethylated histone H3K79.Ehrentraut S et al
121235822002Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain.Feng Q et al
156321262005The DNA damage checkpoint response requires histone H2B ubiquitination by Rad6-Bre1 and H3 methylation by Dot1.Giannattasio M et al
275351062016Targeting Chromatin Regulators Inhibits Leukemogenic Gene Expression in NPM1 Mutant Leukemia.Kühn MW et al
120973182002Disruptor of telomeric silencing-1 is a chromatin-specific histone H3 methyltransferase.Lacoste N et al
273449472016Epigenetic Perturbations by Arg882-Mutated DNMT3A Potentiate Aberrant Stem Cell Gene-Expression Program and Acute Leukemia Development.Lu R et al
274348262016Identification of phenoxyacetamide derivatives as novel DOT1L inhibitors via docking screening and molecular dynamics simulation.Luo M et al
120800902002Lysine methylation within the globular domain of histone H3 by Dot1 is important for telomeric silencing and Sir protein association.Ng HH et al
158510252005hDOT1L links histone methylation to leukemogenesis.Okada Y et al
273352782016DOT1L as a therapeutic target for the treatment of DNMT3A-mutant acute myeloid leukemia.Rau RE et al
269276742016MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemia.Riedel SS et al
250921432014Primary acute myeloid leukemia cells with IDH1 or IDH2 mutations respond to a DOT1L inhibitor in vitro.Sarkaria SM et al
196829342009Linking cell cycle to histone modifications: SBF and H2B monoubiquitination machinery and cell-cycle regulation of H3K79 dimethylation.Schulze JM et al
153713512005Characterization of the grappa gene, the Drosophila histone H3 lysine 79 methyltransferase.Shanower GA et al
274853862016New small molecule inhibitors of histone methyl transferase DOT1L with a nitrile as a non-traditional replacement for heavy halogen atoms.Spurr SS et al
214740732011Dot1 and histone H3K79 methylation in natural telomeric and HM silencing.Takahashi YH et al
267286202016The upstreams and downstreams of H3K79 methylation by DOT1L.Vlaming H et al
239455872013lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs.Yang L et al
219365312011Selective inhibitors of histone methyltransferase DOT1L: design, synthesis, and crystallographic studies.Yao Y et al
253979012015Structure-guided DOT1L probe optimization by label-free ligand displacement.Yi JS et al
234336702013Bromo-deaza-SAH: a potent and selective DOT1L inhibitor.Yu W et al
253597652014Inhibition of histone H3K79 methylation selectively inhibits proliferation, self-renewal and metastatic potential of breast cancer.Zhang L et al
145723102004Structure and regulation of the mDot1 gene, a mouse histone H3 methyltransferase.Zhang W et al
120866732002Dot1p modulates silencing in yeast by methylation of the nucleosome core.van Leeuwen F et al

Other Information

Locus ID:

NCBI: 84444
MIM: 607375
HGNC: 24948
Ensembl: ENSG00000104885

Variants:

dbSNP: 84444
ClinVar: 84444
TCGA: ENSG00000104885
COSMIC: DOT1L

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000104885ENST00000398665Q8TEK3
ENSG00000104885ENST00000446286H7C3N3
ENSG00000104885ENST00000452696C9JH95
ENSG00000104885ENST00000457590H7C2S2
ENSG00000104885ENST00000478937A0A087X1A7
ENSG00000104885ENST00000586024V9GY76

Expression (GTEx)

0
50
100
150

Pathways

PathwaySourceExternal ID
Lysine degradationKEGGko00310
Lysine degradationKEGGhsa00310
Transcriptional misregulation in cancerKEGGko05202
Transcriptional misregulation in cancerKEGGhsa05202
Chromatin organizationREACTOMER-HSA-4839726
Chromatin modifying enzymesREACTOMER-HSA-3247509
PKMTs methylate histone lysinesREACTOMER-HSA-3214841

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA444552HypertensionDiseaseClinicalAnnotationassociatedPD22440088, 31327267
PA448765candesartanChemicalClinicalAnnotationassociatedPD31327267
PA449899hydrochlorothiazideChemicalClinicalAnnotationassociatedPD22440088

References

Pubmed IDYearTitleCitations
217415972011MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L.307
158510252005hDOT1L links histone methylation to leukemogenesis.279
182854652008DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells.194
184491902008Chemically ubiquitylated histone H2B stimulates hDot1L-mediated intranucleosomal methylation.163
178556332007A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification.160
202031302010Linking H3K79 trimethylation to Wnt signaling through a novel Dot1-containing complex (DotCom).119
248164052014IL-22(+)CD4(+) T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L.111
254171072014AF9 YEATS domain links histone acetylation to DOT1L-mediated H3K79 methylation.103
202085222010Disulfide-directed histone ubiquitylation reveals plasticity in hDot1L activation.84
225666242012Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis.56

Citation

Kathrin M. Bernt ; Tobias Neff

DOT1L (DOT1 like histone H3K79 methyltransferase)

Atlas Genet Cytogenet Oncol Haematol. 2016-08-01

Online version: http://atlasgeneticsoncology.org/gene/43797/dot1l