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DOT1L (DOT1 like histone H3K79 methyltransferase)

Written2016-08Kathrin M. Bernt, Tobias Neff
Pediatric Hematology/Oncology/BMT, University of Colorado, Aurora, CO, USA; Kathrin.Bernt@ucdenver.edu; Tobias.Neff@ucdenver.edu

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.

Keywords DOT1L, Epigenetics, Methyltransferase, Leukemia

(Note : for Links provided by Atlas : click)

Identity

Alias_namesDOT1-like
Alias_symbol (synonym)KIAA1814
DOT1
KMT4
Other alias
HGNC (Hugo) DOT1L
LocusID (NCBI) 84444
Atlas_Id 43797
Location 19p13.3. GRCh38.p7 NC_000019.10 (2163963..2232578)  [Link to chromosome band 19p13]
Location_base_pair Starts at 2164149 and ends at 2232578 bp from pter ( according to hg19-Feb_2009)  [Mapping DOT1L.png]
 
  Gene neighbours of DOT1L on chromosome 19p13.3 (NCBI Homo sapiens Annotation Release 108).
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

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).

Protein

 
  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 <1% to the low single digit range (source: Cosmic). The functional significance of DOT1L to the best of our knowledge is unknown.

Implicated in

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 Acute myeloid leukaemia (AML)
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 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 Breast Cancer
Note DOT1L has been suggested as a therapeutic target in breast cancer (Zhang, L. et al., 2014).
  

Bibliography

19682934
DOT1L-HES6 fusion drives androgen independent growth in prostate cancer
Annala M, Kivinummi K, Leinonen K, Tuominen J, Zhang W, Visakorpi T, Nykter M
EMBO Mol Med 2014 Jul 8;6(9):1121-3
PMID 25006183
 
MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L
Bernt KM, Zhu N, Sinha AU, Vempati S, Faber J, Krivtsov AV, Feng Z, Punt N, Daigle A, Bullinger L, Pollock RM, Richon VM, Kung AL, Armstrong SA
Cancer Cell 2011 Jul 12;20(1):66-78
PMID 21741597
 
Abrogation of MLL-AF10 and CALM-AF10-mediated transformation through genetic inactivation or pharmacological inhibition of the H3K79 methyltransferase Dot1l
Chen L, Deshpande AJ, Banka D, Bernt KM, Dias S, Buske C, Olhava EJ, Daigle SR, Richon VM, Pollock RM, Armstrong SA
Leukemia 2013 Apr;27(4):813-22
PMID 23138183
 
Identification of Novel Disruptor of Telomeric Silencing 1-like (DOT1L) Inhibitors through Structure-Based Virtual Screening and Biological Assays
Chen S, Li L, Chen Y, Hu J, Liu J, Liu YC, Liu R, Zhang Y, Meng F, Zhu K, Lu J, Zheng M, Chen K, Zhang J, Jiang H, Yao Z, Luo C
J Chem Inf Model 2016 Mar 28;56(3):527-34
PMID 26914852
 
Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor
Daigle SR, Olhava EJ, Therkelsen CA, Majer CR, Sneeringer CJ, Song J, Johnston LD, Scott MP, Smith JJ, Xiao Y, Jin L, Kuntz KW, Chesworth R, Moyer MP, Bernt KM, Tseng JC, Kung AL, Armstrong SA, Copeland RA, Richon VM, Pollock RM
Cancer Cell 2011 Jul 12;20(1):53-65
PMID 21741596
 
Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l
Deshpande AJ, Chen L, Fazio M, Sinha AU, Bernt KM, Banka D, Dias S, Chang J, Olhava EJ, Daigle SR, Richon VM, Pollock RM, Armstrong SA
Blood 2013 Mar 28;121(13):2533-41
PMID 23361907
 
Exome sequencing reveals three novel candidate predisposition genes for diffuse gastric cancer
Donner I, Kiviluoto T, Ristimäki A, Aaltonen LA, Vahteristo P
Fam Cancer 2015 Jun;14(2):241-6
PMID 25576241
 
Structural basis for the role of the Sir3 AAA+ domain in silencing: interaction with Sir4 and unmethylated histone H3K79
Ehrentraut S, Hassler M, Oppikofer M, Kueng S, Weber JM, Mueller JW, Gasser SM, Ladurner AG, Ehrenhofer-Murray AE
Genes Dev 2011 Sep 1;25(17):1835-46
PMID 21896656
 
Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain
Feng Q, Wang H, Ng HH, Erdjument-Bromage H, Tempst P, Struhl K, Zhang Y
Curr Biol 2002 Jun 25;12(12):1052-8
PMID 12123582
 
The DNA damage checkpoint response requires histone H2B ubiquitination by Rad6-Bre1 and H3 methylation by Dot1
Giannattasio M, Lazzaro F, Plevani P, Muzi-Falconi M
J Biol Chem 2005 Mar 18;280(11):9879-86
PMID 15632126
 
Targeting Chromatin Regulators Inhibits Leukemogenic Gene Expression in NPM1 Mutant Leukemia
Kühn MW, Song E, Feng Z, Sinha A, Chen CW, Deshpande AJ, Cusan M, Farnoud N, Mupo A, Grove C, Koche R, Bradner JE, de Stanchina E, Vassiliou GS, Hoshii T, Armstrong SA
Cancer Discov 2016 Aug 17
PMID 27535106
 
Disruptor of telomeric silencing-1 is a chromatin-specific histone H3 methyltransferase
Lacoste N, Utley RT, Hunter JM, Poirier GG, Côte J
J Biol Chem 2002 Aug 23;277(34):30421-4
PMID 12097318
 
Epigenetic Perturbations by Arg882-Mutated DNMT3A Potentiate Aberrant Stem Cell Gene-Expression Program and Acute Leukemia Development
Lu R, Wang P, Parton T, Zhou Y, Chrysovergis K, Rockowitz S, Chen WY, Abdel-Wahab O, Wade PA, Zheng D, Wang GG
Cancer Cell 2016 Jul 11;30(1):92-107
PMID 27344947
 
Identification of phenoxyacetamide derivatives as novel DOT1L inhibitors via docking screening and molecular dynamics simulation
Luo M, Wang H, Zou Y, Zhang S, Xiao J, Jiang G, Zhang Y, Lai Y
J Mol Graph Model 2016 Jul;68:128-39
PMID 27434826
 
Lysine methylation within the globular domain of histone H3 by Dot1 is important for telomeric silencing and Sir protein association
Ng HH, Feng Q, Wang H, Erdjument-Bromage H, Tempst P, Zhang Y, Struhl K
Genes Dev 2002 Jun 15;16(12):1518-27
PMID 12080090
 
hDOT1L links histone methylation to leukemogenesis
Okada Y, Feng Q, Lin Y, Jiang Q, Li Y, Coffield VM, Su L, Xu G, Zhang Y
Cell 2005 Apr 22;121(2):167-78
PMID 15851025
 
DOT1L as a therapeutic target for the treatment of DNMT3A-mutant acute myeloid leukemia
Rau RE, Rodriguez BA, Luo M, Jeong M, Rosen A, Rogers JH, Campbell CT, Daigle SR, Deng L, Song Y, Sweet S, Chevassut T, Andreeff M, Kornblau SM, Li W, Goodell MA
Blood 2016 Aug 18;128(7):971-81
PMID 27335278
 
MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemia
Riedel SS, Haladyna JN, Bezzant M, Stevens B, Pollyea DA, Sinha AU, Armstrong SA, Wei Q, Pollock RM, Daigle SR, Jordan CT, Ernst P, Neff T, Bernt KM
J Clin Invest 2016 Apr 1;126(4):1438-50
PMID 26927674
 
Primary acute myeloid leukemia cells with IDH1 or IDH2 mutations respond to a DOT1L inhibitor in vitro
Sarkaria SM, Christopher MJ, Klco JM, Ley TJ
Leukemia 2014 Dec;28(12):2403-6
PMID 25092143
 
Linking cell cycle to histone modifications: SBF and H2B monoubiquitination machinery and cell-cycle regulation of H3K79 dimethylation
Schulze JM, Jackson J, Nakanishi S, Gardner JM, Hentrich T, Haug J, Johnston M, Jaspersen SL, Kobor MS, Shilatifard A
Mol Cell 2009 Sep 11;35(5):626-41
 
Characterization of the grappa gene, the Drosophila histone H3 lysine 79 methyltransferase
Shanower GA, Muller M, Blanton JL, Honti V, Gyurkovics H, Schedl P
Genetics 2005 Jan;169(1):173-84
PMID 15371351
 
New small molecule inhibitors of histone methyl transferase DOT1L with a nitrile as a non-traditional replacement for heavy halogen atoms
Spurr SS, Bayle ED, Yu W, Li F, Tempel W, Vedadi M, Schapira M, Fish PV
Bioorg Med Chem Lett 2016 Sep 15;26(18):4518-22
PMID 27485386
 
Dot1 and histone H3K79 methylation in natural telomeric and HM silencing
Takahashi YH, Schulze JM, Jackson J, Hentrich T, Seidel C, Jaspersen SL, Kobor MS, Shilatifard A
Mol Cell 2011 Apr 8;42(1):118-26
PMID 21474073
 
The upstreams and downstreams of H3K79 methylation by DOT1L
Vlaming H, van Leeuwen F
Chromosoma 2016 Sep;125(4):593-605
PMID 26728620
 
lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs
Yang L, Lin C, Jin C, Yang JC, Tanasa B, Li W, Merkurjev D, Ohgi KA, Meng D, Zhang J, Evans CP, Rosenfeld MG
Nature 2013 Aug 29;500(7464):598-602
PMID 23945587
 
Selective inhibitors of histone methyltransferase DOT1L: design, synthesis, and crystallographic studies
Yao Y, Chen P, Diao J, Cheng G, Deng L, Anglin JL, Prasad BV, Song Y
J Am Chem Soc 2011 Oct 26;133(42):16746-9
PMID 21936531
 
Structure-guided DOT1L probe optimization by label-free ligand displacement
Yi JS, Federation AJ, Qi J, Dhe-Paganon S, Hadler M, Xu X, St Pierre R, Varca AC, Wu L, Marineau JJ, Smith WB, Souza A, Chory EJ, Armstrong SA, Bradner JE
ACS Chem Biol 2015 Mar 20;10(3):667-74
PMID 25397901
 
Bromo-deaza-SAH: a potent and selective DOT1L inhibitor
Yu W, Smil D, Li F, Tempel W, Fedorov O, Nguyen KT, Bolshan Y, Al-Awar R, Knapp S, Arrowsmith CH, Vedadi M, Brown PJ, Schapira M
Bioorg Med Chem 2013 Apr 1;21(7):1787-94
PMID 23433670
 
Inhibition of histone H3K79 methylation selectively inhibits proliferation, self-renewal and metastatic potential of breast cancer
Zhang L, Deng L, Chen F, Yao Y, Wu B, Wei L, Mo Q, Song Y
Oncotarget 2014 Nov 15;5(21):10665-77
PMID 25359765
 
Structure and regulation of the mDot1 gene, a mouse histone H3 methyltransferase
Zhang W, Hayashizaki Y, Kone BC
Biochem J 2004 Feb 1;377(Pt 3):641-51
PMID 14572310
 
Dot1p modulates silencing in yeast by methylation of the nucleosome core
van Leeuwen F, Gafken PR, Gottschling DE
Cell 2002 Jun 14;109(6):745-56
PMID 12086673
 

Citation

This paper should be referenced as such :
Bernt KM, Neff T
DOT1L (DOT1 like histone H3K79 methyltransferase);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/DOT1LID43797ch19p13.html


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(4;11)(q21;q23) KMT2A/AFF1


External links

Nomenclature
HGNC (Hugo)DOT1L   24948
Cards
AtlasDOT1LID43797ch19p13.txt
Entrez_Gene (NCBI)DOT1L  84444  DOT1 like histone lysine methyltransferase
AliasesDOT1; KMT4
GeneCards (Weizmann)DOT1L
Ensembl hg19 (Hinxton)ENSG00000104885 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000104885 [Gene_View]  chr19:2164149-2232578 [Contig_View]  DOT1L [Vega]
ICGC DataPortalENSG00000104885
TCGA cBioPortalDOT1L
AceView (NCBI)DOT1L
Genatlas (Paris)DOT1L
WikiGenes84444
SOURCE (Princeton)DOT1L
Genetics Home Reference (NIH)DOT1L
Genomic and cartography
GoldenPath hg38 (UCSC)DOT1L  -     chr19:2164149-2232578 +  19p13.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)DOT1L  -     19p13.3   [Description]    (hg19-Feb_2009)
EnsemblDOT1L - 19p13.3 [CytoView hg19]  DOT1L - 19p13.3 [CytoView hg38]
Mapping of homologs : NCBIDOT1L [Mapview hg19]  DOT1L [Mapview hg38]
OMIM607375   
Gene and transcription
Genbank (Entrez)AB058717 AF509504 AK074120 AK095280 AL080221
RefSeq transcript (Entrez)NM_032482
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)DOT1L
Cluster EST : UnigeneHs.713641 [ NCBI ]
CGAP (NCI)Hs.713641
Alternative Splicing GalleryENSG00000104885
Gene ExpressionDOT1L [ NCBI-GEO ]   DOT1L [ EBI - ARRAY_EXPRESS ]   DOT1L [ SEEK ]   DOT1L [ MEM ]
Gene Expression Viewer (FireBrowse)DOT1L [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)84444
GTEX Portal (Tissue expression)DOT1L
Human Protein AtlasENSG00000104885-DOT1L [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ8TEK3   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ8TEK3  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ8TEK3
Splice isoforms : SwissVarQ8TEK3
Catalytic activity : Enzyme2.1.1.43 [ Enzyme-Expasy ]   2.1.1.432.1.1.43 [ IntEnz-EBI ]   2.1.1.43 [ BRENDA ]   2.1.1.43 [ KEGG ]   
PhosPhoSitePlusQ8TEK3
Domaine pattern : Prosite (Expaxy)DOT1 (PS51569)   
Domains : Interpro (EBI)DOT1_dom    DOT1L/grappa    H3-K79_meTrfase    SAM-dependent_MTases   
Domain families : Pfam (Sanger)DOT1 (PF08123)   
Domain families : Pfam (NCBI)pfam08123   
Conserved Domain (NCBI)DOT1L
DMDM Disease mutations84444
Blocks (Seattle)DOT1L
PDB (SRS)1NW3    2MV7    3QOW    3QOX    3SR4    3SX0    3UWP    4EK9    4EKG    4EKI    4EQZ    4ER0    4ER3    4ER5    4ER6    4ER7    4HRA    4WVL    5DRT    5DRY    5DSX    5DT2    5DTM    5DTQ    5DTR    5JUW   
PDB (PDBSum)1NW3    2MV7    3QOW    3QOX    3SR4    3SX0    3UWP    4EK9    4EKG    4EKI    4EQZ    4ER0    4ER3    4ER5    4ER6    4ER7    4HRA    4WVL    5DRT    5DRY    5DSX    5DT2    5DTM    5DTQ    5DTR    5JUW   
PDB (IMB)1NW3    2MV7    3QOW    3QOX    3SR4    3SX0    3UWP    4EK9    4EKG    4EKI    4EQZ    4ER0    4ER3    4ER5    4ER6    4ER7    4HRA    4WVL    5DRT    5DRY    5DSX    5DT2    5DTM    5DTQ    5DTR    5JUW   
PDB (RSDB)1NW3    2MV7    3QOW    3QOX    3SR4    3SX0    3UWP    4EK9    4EKG    4EKI    4EQZ    4ER0    4ER3    4ER5    4ER6    4ER7    4HRA    4WVL    5DRT    5DRY    5DSX    5DT2    5DTM    5DTQ    5DTR    5JUW   
Structural Biology KnowledgeBase1NW3    2MV7    3QOW    3QOX    3SR4    3SX0    3UWP    4EK9    4EKG    4EKI    4EQZ    4ER0    4ER3    4ER5    4ER6    4ER7    4HRA    4WVL    5DRT    5DRY    5DSX    5DT2    5DTM    5DTQ    5DTR    5JUW   
SCOP (Structural Classification of Proteins)1NW3    2MV7    3QOW    3QOX    3SR4    3SX0    3UWP    4EK9    4EKG    4EKI    4EQZ    4ER0    4ER3    4ER5    4ER6    4ER7    4HRA    4WVL    5DRT    5DRY    5DSX    5DT2    5DTM    5DTQ    5DTR    5JUW   
CATH (Classification of proteins structures)1NW3    2MV7    3QOW    3QOX    3SR4    3SX0    3UWP    4EK9    4EKG    4EKI    4EQZ    4ER0    4ER3    4ER5    4ER6    4ER7    4HRA    4WVL    5DRT    5DRY    5DSX    5DT2    5DTM    5DTQ    5DTR    5JUW   
SuperfamilyQ8TEK3
Human Protein Atlas [tissue]ENSG00000104885-DOT1L [tissue]
Peptide AtlasQ8TEK3
HPRD10455
IPIIPI00873164   IPI00289034   IPI00880197   IPI00878011   IPI00877878   IPI00878344   
Protein Interaction databases
DIP (DOE-UCLA)Q8TEK3
IntAct (EBI)Q8TEK3
FunCoupENSG00000104885
BioGRIDDOT1L
STRING (EMBL)DOT1L
ZODIACDOT1L
Ontologies - Pathways
QuickGOQ8TEK3
Ontology : AmiGODNA damage checkpoint  chromosome, telomeric region  DNA binding  protein binding  nucleus  nucleoplasm  nucleoplasm  DNA repair  chromatin silencing at telomere  positive regulation of cell proliferation  histone-lysine N-methyltransferase activity  histone-lysine N-methyltransferase activity  histone methyltransferase activity (H3-K79 specific)  telomere organization  histone H3-K79 methylation  histone methyltransferase activity  intracellular membrane-bounded organelle  protein complex  positive regulation of transcription from RNA polymerase II promoter  regulation of JAK-STAT cascade  regulation of transcription regulatory region DNA binding  
Ontology : EGO-EBIDNA damage checkpoint  chromosome, telomeric region  DNA binding  protein binding  nucleus  nucleoplasm  nucleoplasm  DNA repair  chromatin silencing at telomere  positive regulation of cell proliferation  histone-lysine N-methyltransferase activity  histone-lysine N-methyltransferase activity  histone methyltransferase activity (H3-K79 specific)  telomere organization  histone H3-K79 methylation  histone methyltransferase activity  intracellular membrane-bounded organelle  protein complex  positive regulation of transcription from RNA polymerase II promoter  regulation of JAK-STAT cascade  regulation of transcription regulatory region DNA binding  
Pathways : KEGGLysine degradation    Transcriptional misregulation in cancer   
REACTOMEQ8TEK3 [protein]
REACTOME PathwaysR-HSA-3214841 [pathway]   
NDEx NetworkDOT1L
Atlas of Cancer Signalling NetworkDOT1L
Wikipedia pathwaysDOT1L
Orthology - Evolution
OrthoDB84444
GeneTree (enSembl)ENSG00000104885
Phylogenetic Trees/Animal Genes : TreeFamDOT1L
HOVERGENQ8TEK3
HOGENOMQ8TEK3
Homologs : HomoloGeneDOT1L
Homology/Alignments : Family Browser (UCSC)DOT1L
Gene fusions - Rearrangements
Fusion : MitelmanDOT1L/CSNK1G2 [19p13.3/19p13.3]  
Fusion : MitelmanDOT1L/EPB41L2 [19p13.3/6q23.1]  [t(6;19)(q23;p13)]  
Fusion : MitelmanDOT1L/ONECUT3 [19p13.3/19p13.3]  [t(19;19)(p13;p13)]  
Fusion : MitelmanHIVEP3/DOT1L [1p34.2/19p13.3]  [t(1;19)(p34;p13)]  
Fusion: TCGADOT1L 19p13.3 EPB41L2 6q23.1 BRCA
Fusion: TCGADOT1L 19p13.3 ONECUT3 19p13.3 KIRC
Fusion: TCGAHIVEP3 1p34.2 DOT1L 19p13.3 SKCM
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerDOT1L [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)DOT1L
dbVarDOT1L
ClinVarDOT1L
1000_GenomesDOT1L 
Exome Variant ServerDOT1L
ExAC (Exome Aggregation Consortium)ENSG00000104885
GNOMAD BrowserENSG00000104885
Genetic variants : HAPMAP84444
Genomic Variants (DGV)DOT1L [DGVbeta]
DECIPHERDOT1L [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisDOT1L 
Mutations
ICGC Data PortalDOT1L 
TCGA Data PortalDOT1L 
Broad Tumor PortalDOT1L
OASIS PortalDOT1L [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICDOT1L  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDDOT1L
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch DOT1L
DgiDB (Drug Gene Interaction Database)DOT1L
DoCM (Curated mutations)DOT1L (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)DOT1L (select a term)
intoGenDOT1L
NCG5 (London)DOT1L
Cancer3DDOT1L(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM607375   
Orphanet
MedgenDOT1L
Genetic Testing Registry DOT1L
NextProtQ8TEK3 [Medical]
TSGene84444
GENETestsDOT1L
Target ValidationDOT1L
Huge Navigator DOT1L [HugePedia]
snp3D : Map Gene to Disease84444
BioCentury BCIQDOT1L
ClinGenDOT1L
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD84444
Chemical/Pharm GKB GenePA134993717
Clinical trialDOT1L
Miscellaneous
canSAR (ICR)DOT1L (select the gene name)
Other databaseDOT1L ExAC
Probes
Litterature
PubMed70 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineDOT1L
EVEXDOT1L
GoPubMedDOT1L
iHOPDOT1L
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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