SET1A_HUMAN
ID SET1A_HUMAN Reviewed; 1707 AA.
AC O15047; A6NP62; Q6PIF3; Q8TAJ6;
DT 21-JUN-2005, integrated into UniProtKB/Swiss-Prot.
DT 21-JUN-2005, sequence version 3.
DT 03-AUG-2022, entry version 190.
DE RecName: Full=Histone-lysine N-methyltransferase SETD1A;
DE EC=2.1.1.364 {ECO:0000269|PubMed:25561738, ECO:0000269|PubMed:29937342};
DE AltName: Full=Lysine N-methyltransferase 2F;
DE AltName: Full=SET domain-containing protein 1A;
DE Short=hSET1A;
DE AltName: Full=Set1/Ash2 histone methyltransferase complex subunit SET1;
GN Name=SETD1A;
GN Synonyms=KIAA0339 {ECO:0000312|EMBL:BAA20797.2}, KMT2F, SET1, SET1A;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1] {ECO:0000312|EMBL:BAA20797.2}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain {ECO:0000312|EMBL:BAA20797.2};
RX PubMed=9205841; DOI=10.1093/dnares/4.2.141;
RA Nagase T., Ishikawa K., Nakajima D., Ohira M., Seki N., Miyajima N.,
RA Tanaka A., Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. VII. The
RT complete sequences of 100 new cDNA clones from brain which can code for
RT large proteins in vitro.";
RL DNA Res. 4:141-150(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G.,
RA Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E.,
RA Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M.,
RA Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C.,
RA Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M.,
RA Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M.,
RA Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D.,
RA Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L.,
RA Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E.,
RA Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H.,
RA Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y.,
RA Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S.,
RA Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A.,
RA Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M.,
RA Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H.,
RA Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A.,
RA Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J.,
RA DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J.,
RA Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M.,
RA Myers R.M., Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-248 AND 1239-1707.
RC TISSUE=Brain {ECO:0000312|EMBL:AAH27450.1}, and
RC Duodenum {ECO:0000312|EMBL:AAH35795.1};
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP FUNCTION, AND INTERACTION WITH HCFC1.
RX PubMed=12670868; DOI=10.1101/gad.252103;
RA Wysocka J., Myers M.P., Laherty C.D., Eisenman R.N., Herr W.;
RT "Human Sin3 deacetylase and trithorax-related Set1/Ash2 histone H3-K4
RT methyltransferase are tethered together selectively by the cell-
RT proliferation factor HCF-1.";
RL Genes Dev. 17:896-911(2003).
RN [5]
RP IDENTIFICATION IN THE SET1 COMPLEX.
RX PubMed=16253997; DOI=10.1074/jbc.m508312200;
RA Lee J.-H., Skalnik D.G.;
RT "CpG-binding protein (CXXC finger protein 1) is a component of the
RT mammalian Set1 histone H3-Lys4 methyltransferase complex, the analogue of
RT the yeast Set1/COMPASS complex.";
RL J. Biol. Chem. 280:41725-41731(2005).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT networks.";
RL Cell 127:635-648(2006).
RN [7]
RP SUBCELLULAR LOCATION, AND IDENTIFICATION IN THE SET1 COMPLEX.
RX PubMed=17355966; DOI=10.1074/jbc.m609809200;
RA Lee J.-H., Tate C.M., You J.-S., Skalnik D.G.;
RT "Identification and characterization of the human Set1B histone H3-Lys4
RT methyltransferase complex.";
RL J. Biol. Chem. 282:13419-13428(2007).
RN [8]
RP IDENTIFICATION IN SET1 COMPLEX, AND INTERACTION WITH ASH2L; RBBP5; CXXC1;
RP HCFC1; WDR5; WDR82 AND POLR2A.
RX PubMed=17998332; DOI=10.1128/mcb.01356-07;
RA Lee J.H., Skalnik D.G.;
RT "Wdr82 is a C-terminal domain-binding protein that recruits the Setd1A
RT Histone H3-Lys4 methyltransferase complex to transcription start sites of
RT transcribed human genes.";
RL Mol. Cell. Biol. 28:609-618(2008).
RN [9]
RP IDENTIFICATION IN SET1 COMPLEX.
RX PubMed=18838538; DOI=10.1128/mcb.00976-08;
RA Wu M., Wang P.F., Lee J.S., Martin-Brown S., Florens L., Washburn M.,
RA Shilatifard A.;
RT "Molecular regulation of H3K4 trimethylation by Wdr82, a component of human
RT Set1/COMPASS.";
RL Mol. Cell. Biol. 28:7337-7344(2008).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-508, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [15]
RP INTERACTION WITH ZNF335.
RX PubMed=23178126; DOI=10.1016/j.cell.2012.10.043;
RA Yang Y.J., Baltus A.E., Mathew R.S., Murphy E.A., Evrony G.D.,
RA Gonzalez D.M., Wang E.P., Marshall-Walker C.A., Barry B.J., Murn J.,
RA Tatarakis A., Mahajan M.A., Samuels H.H., Shi Y., Golden J.A., Mahajnah M.,
RA Shenhav R., Walsh C.A.;
RT "Microcephaly gene links trithorax and REST/NRSF to control neural stem
RT cell proliferation and differentiation.";
RL Cell 151:1097-1112(2012).
RN [16]
RP INTERACTION WITH SUPT6H.
RX PubMed=22843687; DOI=10.1074/jbc.m112.351569;
RA Begum N.A., Stanlie A., Nakata M., Akiyama H., Honjo T.;
RT "The histone chaperone Spt6 is required for activation-induced cytidine
RT deaminase target determination through H3K4me3 regulation.";
RL J. Biol. Chem. 287:32415-32429(2012).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-459; SER-464; SER-565 AND
RP SER-915, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [18]
RP IDENTIFICATION IN SET1A COMPLEX.
RX PubMed=23508102; DOI=10.1128/mcb.01742-12;
RA van Nuland R., Smits A.H., Pallaki P., Jansen P.W., Vermeulen M.,
RA Timmers H.T.;
RT "Quantitative dissection and stoichiometry determination of the human
RT SET1/MLL histone methyltransferase complexes.";
RL Mol. Cell. Biol. 33:2067-2077(2013).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1103, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [20]
RP FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, AND MUTAGENESIS OF ASN-1646.
RX PubMed=25561738; DOI=10.1074/jbc.m114.627646;
RA Shinsky S.A., Monteith K.E., Viggiano S., Cosgrove M.S.;
RT "Biochemical reconstitution and phylogenetic comparison of human SET1
RT family core complexes involved in histone methylation.";
RL J. Biol. Chem. 290:6361-6375(2015).
RN [21]
RP FUNCTION, CATALYTIC ACTIVITY, AND INTERACTION WITH BOD1L1.
RX PubMed=29937342; DOI=10.1016/j.molcel.2018.05.018;
RA Higgs M.R., Sato K., Reynolds J.J., Begum S., Bayley R., Goula A.,
RA Vernet A., Paquin K.L., Skalnik D.G., Kobayashi W., Takata M.,
RA Howlett N.G., Kurumizaka H., Kimura H., Stewart G.S.;
RT "Histone Methylation by SETD1A Protects Nascent DNA through the Nucleosome
RT Chaperone Activity of FANCD2.";
RL Mol. Cell 71:25-41(2018).
RN [22]
RP INVOLVEMENT IN EPEDD, VARIANTS EPEDD ARG-269; CYS-913; ARG-1369 AND
RP HIS-1392, CHARACTERIZATION OF VARIANTS EPEDD ARG-269; CYS-913; ARG-1369 AND
RP HIS-1392, AND FUNCTION.
RX PubMed=31197650; DOI=10.1007/s12264-019-00400-w;
RA Yu X., Yang L., Li J., Li W., Li D., Wang R., Wu K., Chen W., Zhang Y.,
RA Qiu Z., Zhou W.;
RT "De novo and inherited SETD1A variants in early-onset epilepsy.";
RL Neurosci. Bull. 35:1045-1057(2019).
RN [23]
RP INVOLVEMENT IN NEDSID, VARIANTS NEDSID 37-GLN--ASN-1707 DEL;
RP 455-GLU--ASN-1707 DEL; 499-GLN--ASN-1707 DEL; 909-GLU--ASN-1707 DEL;
RP 990-ARG--ASN-1707 DEL AND ASP-1499, CHARACTERIZATION OF VARIANT ASP-1499,
RP AND FUNCTION.
RX PubMed=32346159; DOI=10.1038/s41380-020-0725-5;
RA Kummeling J., Stremmelaar D.E., Raun N., Reijnders M.R.F., Willemsen M.H.,
RA Ruiterkamp-Versteeg M., Schepens M., Man C.C.O., Gilissen C., Cho M.T.,
RA McWalter K., Sinnema M., Wheless J.W., Simon M.E.H., Genetti C.A.,
RA Casey A.M., Terhal P.A., van der Smagt J.J., van Gassen K.L.I., Joset P.,
RA Bahr A., Steindl K., Rauch A., Keller E., Raas-Rothschild A., Koolen D.A.,
RA Agrawal P.B., Hoffman T.L., Powell-Hamilton N.N., Thiffault I.,
RA Engleman K., Zhou D., Bodamer O., Hoefele J., Riedhammer K.M.,
RA Schwaibold E.M.C., Tasic V., Schubert D., Top D., Pfundt R., Higgs M.R.,
RA Kramer J.M., Kleefstra T.;
RT "Characterization of SETD1A haploinsufficiency in humans and Drosophila
RT defines a novel neurodevelopmental syndrome.";
RL Mol. Psychiatry 26:2013-2024(2021).
RN [24] {ECO:0007744|PDB:4EWR}
RP X-RAY CRYSTALLOGRAPHY (1.50 ANGSTROMS) OF 1488-1501 IN COMPLEX WITH WDR5,
RP INTERACTION WITH WDR5, AND MOTIF WIN.
RX PubMed=22665483; DOI=10.1074/jbc.m112.364125;
RA Dharmarajan V., Lee J.H., Patel A., Skalnik D.G., Cosgrove M.S.;
RT "Structural basis for WDR5 interaction (Win) motif recognition in human
RT SET1 family histone methyltransferases.";
RL J. Biol. Chem. 287:27275-27289(2012).
RN [25] {ECO:0007744|PDB:3UVN}
RP X-RAY CRYSTALLOGRAPHY (1.79 ANGSTROMS) OF 1492-1502 IN COMPLEX WITH WDR5,
RP INTERACTION WITH WDR5, AND MOTIF WIN.
RX PubMed=22266653; DOI=10.1093/nar/gkr1235;
RA Zhang P., Lee H., Brunzelle J.S., Couture J.F.;
RT "The plasticity of WDR5 peptide-binding cleft enables the binding of the
RT SET1 family of histone methyltransferases.";
RL Nucleic Acids Res. 40:4237-4246(2012).
CC -!- FUNCTION: Histone methyltransferase that catalyzes methyl group
CC transfer from S-adenosyl-L-methionine to the epsilon-amino group of
CC 'Lys-4' of histone H3 (H3K4) via a non-processive mechanism
CC (PubMed:25561738, PubMed:12670868). Part of chromatin remodeling
CC machinery, forms H3K4me1, H3K4me2 and H3K4me3 methylation marks at
CC active chromatin sites where transcription and DNA repair take place
CC (PubMed:29937342, PubMed:31197650, PubMed:32346159). Responsible for
CC H3K4me3 enriched promoters and transcriptional programming of inner
CC mass stem cells and neuron progenitors during embryogenesis (By
CC similarity) (PubMed:31197650). Required for H3K4me1 mark at stalled
CC replication forks. Mediates FANCD2-dependent nucleosome remodeling and
CC RAD51 nucleofilaments stabilization at reversed forks, protecting them
CC from nucleolytic degradation (PubMed:29937342, PubMed:32346159). Does
CC not methylate 'Lys-4' of histone H3 if the neighboring 'Lys-9' residue
CC is already methylated (PubMed:12670868). {ECO:0000250|UniProtKB:E9PYH6,
CC ECO:0000269|PubMed:12670868, ECO:0000269|PubMed:25561738,
CC ECO:0000269|PubMed:29937342, ECO:0000269|PubMed:31197650,
CC ECO:0000269|PubMed:32346159}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-lysyl(4)-[histone H3] + S-adenosyl-L-methionine = H(+) +
CC N(6)-methyl-L-lysyl(4)-[histone H3] + S-adenosyl-L-homocysteine;
CC Xref=Rhea:RHEA:60264, Rhea:RHEA-COMP:15543, Rhea:RHEA-COMP:15547,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:29969, ChEBI:CHEBI:57856,
CC ChEBI:CHEBI:59789, ChEBI:CHEBI:61929; EC=2.1.1.364;
CC Evidence={ECO:0000269|PubMed:25561738, ECO:0000269|PubMed:29937342};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:60265;
CC Evidence={ECO:0000269|PubMed:25561738, ECO:0000269|PubMed:29937342};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=N(6)-methyl-L-lysyl(4)-[histone H3] + S-adenosyl-L-methionine
CC = H(+) + N(6),N(6)-dimethyl-L-lysyl(4)-[histone H3] + S-adenosyl-L-
CC homocysteine; Xref=Rhea:RHEA:60268, Rhea:RHEA-COMP:15540, Rhea:RHEA-
CC COMP:15543, ChEBI:CHEBI:15378, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789,
CC ChEBI:CHEBI:61929, ChEBI:CHEBI:61976;
CC Evidence={ECO:0000269|PubMed:25561738};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:60269;
CC Evidence={ECO:0000269|PubMed:25561738};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=N(6),N(6)-dimethyl-L-lysyl(4)-[histone H3] + S-adenosyl-L-
CC methionine = H(+) + N(6),N(6),N(6)-trimethyl-L-lysyl(4)-[histone H3]
CC + S-adenosyl-L-homocysteine; Xref=Rhea:RHEA:60272, Rhea:RHEA-
CC COMP:15537, Rhea:RHEA-COMP:15540, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:57856, ChEBI:CHEBI:59789, ChEBI:CHEBI:61961,
CC ChEBI:CHEBI:61976; Evidence={ECO:0000269|PubMed:25561738};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:60273;
CC Evidence={ECO:0000269|PubMed:25561738};
CC -!- SUBUNIT: Component of the SET1A complex composed of the catalytic
CC subunit SETD1A, WDR5, WDR82, RBBP5, ASH2L/ASH2, CXXC1/CFP1, HCFC1 and
CC DPY30 homotrimer (PubMed:23508102, PubMed:16253997, PubMed:17355966,
CC PubMed:18838538). Forms a core complex with the evolutionary conserved
CC subcomplex WRAD composed of WDR5, RBBP5, ASH2L/ASH2 and DPY30 subunits;
CC WRAD differentially stimulates the methyltransferase activity
CC (PubMed:23508102, PubMed:25561738). Interacts with BOD1L1 (via COMPASS-
CC Shg1 domain) at replication forks (PubMed:29937342). Interacts with
CC HCFC1 (PubMed:12670868). Interacts with ASH2/ASH2L, CXXC1/CFP1 and
CC RBBP5. Interacts (via the RRM domain) with WDR82. Interacts (via the
CC RRM domain) with hyperphosphorylated C-terminal domain (CTD) of RNA
CC polymerase II large subunit (POLR2A) only in the presence of WDR82.
CC Binds specifically to CTD heptad repeats phosphorylated on 'Ser-5' of
CC each heptad. Interacts with ZNF335. Interacts with SUPT6H
CC (PubMed:22843687). Interacts with NAP1L1 (By similarity). Interacts
CC (via WIN motif) with WDR5 (PubMed:17998332, PubMed:22665483,
CC PubMed:22266653). {ECO:0000250|UniProtKB:E9PYH6,
CC ECO:0000269|PubMed:12670868, ECO:0000269|PubMed:16253997,
CC ECO:0000269|PubMed:17355966, ECO:0000269|PubMed:17998332,
CC ECO:0000269|PubMed:18838538, ECO:0000269|PubMed:22266653,
CC ECO:0000269|PubMed:22665483, ECO:0000269|PubMed:22843687,
CC ECO:0000269|PubMed:23178126, ECO:0000269|PubMed:23508102,
CC ECO:0000269|PubMed:25561738, ECO:0000269|PubMed:29937342}.
CC -!- INTERACTION:
CC O15047; Q9UBL3-3: ASH2L; NbExp=2; IntAct=EBI-540779, EBI-16130425;
CC O15047; P51610: HCFC1; NbExp=2; IntAct=EBI-540779, EBI-396176;
CC O15047; Q15291: RBBP5; NbExp=3; IntAct=EBI-540779, EBI-592823;
CC O15047; Q93009: USP7; NbExp=2; IntAct=EBI-540779, EBI-302474;
CC O15047; Q02248: Ctnnb1; Xeno; NbExp=2; IntAct=EBI-540779, EBI-397872;
CC -!- SUBCELLULAR LOCATION: Nucleus speckle {ECO:0000269|PubMed:17355966}.
CC Chromosome {ECO:0000269|PubMed:17355966}. Note=Localizes to a largely
CC non-overlapping set of euchromatic nuclear speckles with SETD1B,
CC suggesting that SETD1A and SETD1B each bind to a unique set of target
CC genes.
CC -!- DISEASE: Epilepsy, early-onset, with or without developmental delay
CC (EPEDD) [MIM:618832]: An autosomal dominant neurologic disorder
CC characterized by early onset of generalized tonic-clonic seizures
CC associated with sharp wave and sharp slow wave discharges on EEG. Some
CC EPEDD patients have normal psychomotor development and normal brain
CC imaging, whereas others may show developmental delay associated with
CC abnormalities on brain imaging. {ECO:0000269|PubMed:31197650}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Neurodevelopmental disorder with speech impairment and
CC dysmorphic facies (NEDSID) [MIM:619056]: An autosomal dominant disorder
CC characterized by global developmental delay, intellectual disability,
CC speech delay, subtle facial dysmorphism, and behavioral and psychiatric
CC problems. {ECO:0000269|PubMed:32346159}. Note=The disease is caused by
CC variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the class V-like SAM-binding methyltransferase
CC superfamily. {ECO:0000255|PROSITE-ProRule:PRU00190}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH35795.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305};
CC Sequence=BAA20797.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AB002337; BAA20797.2; ALT_INIT; mRNA.
DR EMBL; AC135048; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC027450; AAH27450.1; -; mRNA.
DR EMBL; BC035795; AAH35795.1; ALT_SEQ; mRNA.
DR CCDS; CCDS32435.1; -.
DR RefSeq; NP_055527.1; NM_014712.2.
DR RefSeq; XP_005255780.1; XM_005255723.1.
DR RefSeq; XP_006721169.1; XM_006721106.3.
DR RefSeq; XP_016879398.1; XM_017023909.1.
DR PDB; 3S8S; X-ray; 1.30 A; A=89-197.
DR PDB; 3UVN; X-ray; 1.79 A; B/D=1492-1502.
DR PDB; 4EWR; X-ray; 1.50 A; C=1488-1501.
DR PDBsum; 3S8S; -.
DR PDBsum; 3UVN; -.
DR PDBsum; 4EWR; -.
DR AlphaFoldDB; O15047; -.
DR SMR; O15047; -.
DR BioGRID; 115088; 164.
DR ComplexPortal; CPX-7110; Histone-lysine N-methyltransferase complex, SET1A variant.
DR CORUM; O15047; -.
DR DIP; DIP-33494N; -.
DR ELM; O15047; -.
DR IntAct; O15047; 47.
DR MINT; O15047; -.
DR STRING; 9606.ENSP00000262519; -.
DR ChEMBL; CHEMBL4105954; -.
DR GlyGen; O15047; 6 sites, 1 O-linked glycan (6 sites).
DR iPTMnet; O15047; -.
DR PhosphoSitePlus; O15047; -.
DR BioMuta; SETD1A; -.
DR EPD; O15047; -.
DR jPOST; O15047; -.
DR MassIVE; O15047; -.
DR MaxQB; O15047; -.
DR PaxDb; O15047; -.
DR PeptideAtlas; O15047; -.
DR PRIDE; O15047; -.
DR ProteomicsDB; 48400; -.
DR Antibodypedia; 13862; 213 antibodies from 26 providers.
DR DNASU; 9739; -.
DR Ensembl; ENST00000262519.14; ENSP00000262519.8; ENSG00000099381.19.
DR Ensembl; ENST00000684162.1; ENSP00000507683.1; ENSG00000099381.19.
DR GeneID; 9739; -.
DR KEGG; hsa:9739; -.
DR MANE-Select; ENST00000262519.14; ENSP00000262519.8; NM_014712.3; NP_055527.1.
DR UCSC; uc002ead.2; human.
DR CTD; 9739; -.
DR DisGeNET; 9739; -.
DR GeneCards; SETD1A; -.
DR HGNC; HGNC:29010; SETD1A.
DR HPA; ENSG00000099381; Low tissue specificity.
DR MalaCards; SETD1A; -.
DR MIM; 611052; gene.
DR MIM; 618832; phenotype.
DR MIM; 619056; phenotype.
DR neXtProt; NX_O15047; -.
DR OpenTargets; ENSG00000099381; -.
DR Orphanet; 528084; Non-specific syndromic intellectual disability.
DR PharmGKB; PA128394556; -.
DR VEuPathDB; HostDB:ENSG00000099381; -.
DR eggNOG; KOG1080; Eukaryota.
DR GeneTree; ENSGT00940000154575; -.
DR HOGENOM; CLU_001226_2_0_1; -.
DR InParanoid; O15047; -.
DR OMA; DNGEKDH; -.
DR OrthoDB; 1234689at2759; -.
DR PhylomeDB; O15047; -.
DR TreeFam; TF106436; -.
DR BioCyc; MetaCyc:HS01894-MON; -.
DR BRENDA; 2.1.1.354; 2681.
DR PathwayCommons; O15047; -.
DR Reactome; R-HSA-3214841; PKMTs methylate histone lysines.
DR Reactome; R-HSA-8936459; RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function.
DR SignaLink; O15047; -.
DR SIGNOR; O15047; -.
DR BioGRID-ORCS; 9739; 718 hits in 1099 CRISPR screens.
DR ChiTaRS; SETD1A; human.
DR GenomeRNAi; 9739; -.
DR Pharos; O15047; Tbio.
DR PRO; PR:O15047; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; O15047; protein.
DR Bgee; ENSG00000099381; Expressed in paraflocculus and 157 other tissues.
DR ExpressionAtlas; O15047; baseline and differential.
DR Genevisible; O15047; HS.
DR GO; GO:0000785; C:chromatin; IDA:ParkinsonsUK-UCL.
DR GO; GO:0035097; C:histone methyltransferase complex; IDA:UniProtKB.
DR GO; GO:0016607; C:nuclear speck; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0048188; C:Set1C/COMPASS complex; IDA:UniProtKB.
DR GO; GO:0008013; F:beta-catenin binding; IPI:BHF-UCL.
DR GO; GO:0042800; F:histone methyltransferase activity (H3-K4 specific); IDA:UniProtKB.
DR GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:ParkinsonsUK-UCL.
DR GO; GO:0007420; P:brain development; IMP:UniProtKB.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IEA:UniProtKB-KW.
DR GO; GO:0006325; P:chromatin organization; IEA:UniProtKB-KW.
DR GO; GO:0044648; P:histone H3-K4 dimethylation; IDA:CACAO.
DR GO; GO:0051568; P:histone H3-K4 methylation; IBA:GO_Central.
DR GO; GO:0097692; P:histone H3-K4 monomethylation; IDA:CACAO.
DR GO; GO:0080182; P:histone H3-K4 trimethylation; IDA:CACAO.
DR GO; GO:1902275; P:regulation of chromatin organization; IDA:ParkinsonsUK-UCL.
DR GO; GO:1902036; P:regulation of hematopoietic stem cell differentiation; IDA:ParkinsonsUK-UCL.
DR CDD; cd12548; RRM_Set1A; 1.
DR Gene3D; 2.170.270.10; -; 1.
DR Gene3D; 3.30.70.330; -; 1.
DR IDEAL; IID00358; -.
DR InterPro; IPR024657; COMPASS_Set1_N-SET.
DR InterPro; IPR012677; Nucleotide-bd_a/b_plait_sf.
DR InterPro; IPR003616; Post-SET_dom.
DR InterPro; IPR035979; RBD_domain_sf.
DR InterPro; IPR000504; RRM_dom.
DR InterPro; IPR044570; Set1-like.
DR InterPro; IPR034467; Set1A_RRM.
DR InterPro; IPR001214; SET_dom.
DR InterPro; IPR046341; SET_dom_sf.
DR InterPro; IPR037841; SETD1A.
DR PANTHER; PTHR45814; PTHR45814; 1.
DR PANTHER; PTHR45814:SF3; PTHR45814:SF3; 1.
DR Pfam; PF11764; N-SET; 1.
DR Pfam; PF00076; RRM_1; 1.
DR Pfam; PF00856; SET; 1.
DR SMART; SM01291; N-SET; 1.
DR SMART; SM00508; PostSET; 1.
DR SMART; SM00360; RRM; 1.
DR SMART; SM00317; SET; 1.
DR SUPFAM; SSF54928; SSF54928; 1.
DR SUPFAM; SSF82199; SSF82199; 1.
DR PROSITE; PS50868; POST_SET; 1.
DR PROSITE; PS50102; RRM; 1.
DR PROSITE; PS50280; SET; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Activator; Chromatin regulator; Chromosome; Disease variant;
KW DNA damage; Epilepsy; Intellectual disability; Methyltransferase; Nucleus;
KW Phosphoprotein; Reference proteome; RNA-binding; S-adenosyl-L-methionine;
KW Transcription; Transcription regulation; Transferase.
FT CHAIN 1..1707
FT /note="Histone-lysine N-methyltransferase SETD1A"
FT /id="PRO_0000186056"
FT DOMAIN 84..172
FT /note="RRM"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00176"
FT DOMAIN 1568..1685
FT /note="SET"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00190"
FT DOMAIN 1691..1707
FT /note="Post-SET"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00155"
FT REGION 194..308
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 331..363
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 381..486
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 506..655
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 834..854
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 891..1251
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1264..1293
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1307..1417
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1415..1450
FT /note="Interaction with CFP1"
FT REGION 1450..1537
FT /note="Interaction with ASH2L, RBBP5 and WDR5"
FT /evidence="ECO:0000269|PubMed:17998332"
FT REGION 1472..1499
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 1299..1303
FT /note="HCFC1-binding motif (HBM)"
FT MOTIF 1492..1497
FT /note="WDR5 interaction motif (WIN)"
FT /evidence="ECO:0000269|PubMed:22266653,
FT ECO:0000269|PubMed:22665483"
FT COMPBIAS 206..308
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 427..444
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 463..486
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 565..580
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 593..655
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 892..918
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 929..964
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 971..991
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 992..1015
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1016..1059
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1074..1094
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1120..1161
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1176..1190
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1225..1244
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1310..1325
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1360..1380
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1477..1491
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 459
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 464
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 508
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19690332"
FT MOD_RES 565
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 915
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 1103
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT VARIANT 37..1707
FT /note="Missing (in NEDSID)"
FT /evidence="ECO:0000269|PubMed:32346159"
FT /id="VAR_085029"
FT VARIANT 269
FT /note="Q -> R (in EPEDD; affects the development of
FT synapses in a mouse model overexpressing the human protein
FT harboring this variant)"
FT /evidence="ECO:0000269|PubMed:31197650"
FT /id="VAR_083962"
FT VARIANT 455..1707
FT /note="Missing (in NEDSID)"
FT /evidence="ECO:0000269|PubMed:32346159"
FT /id="VAR_085030"
FT VARIANT 499..1707
FT /note="Missing (in NEDSID)"
FT /evidence="ECO:0000269|PubMed:32346159"
FT /id="VAR_085031"
FT VARIANT 639
FT /note="D -> N (in dbSNP:rs897985)"
FT /id="VAR_059318"
FT VARIANT 909..1707
FT /note="Missing (in NEDSID)"
FT /evidence="ECO:0000269|PubMed:32346159"
FT /id="VAR_085032"
FT VARIANT 913
FT /note="R -> C (in EPEDD; affects the development of
FT synapses in a mouse model overexpressing the human protein
FT harboring this variant)"
FT /evidence="ECO:0000269|PubMed:31197650"
FT /id="VAR_083963"
FT VARIANT 990..1707
FT /note="Missing (in NEDSID)"
FT /evidence="ECO:0000269|PubMed:32346159"
FT /id="VAR_085033"
FT VARIANT 1369
FT /note="G -> R (in EPEDD; affects the development of
FT synapses in a mouse model overexpressing the human protein
FT harboring this variant; dbSNP:rs781482552)"
FT /evidence="ECO:0000269|PubMed:31197650"
FT /id="VAR_083964"
FT VARIANT 1392
FT /note="R -> H (in EPEDD; affects the development of
FT synapses in a mouse model overexpressing the human protein
FT harboring this variant; dbSNP:rs772206552)"
FT /evidence="ECO:0000269|PubMed:31197650"
FT /id="VAR_083965"
FT VARIANT 1499
FT /note="Y -> D (in NEDSID; causes DNA damage repair defects
FT associated with nucleolytic degradation of nascent DNA at
FT stalled replication forks)"
FT /evidence="ECO:0000269|PubMed:32346159"
FT /id="VAR_085008"
FT MUTAGEN 1646
FT /note="N->A: Abolishes interaction with S-adenosyl-L-
FT methionine."
FT /evidence="ECO:0000269|PubMed:25561738"
FT CONFLICT 242..248
FT /note="PCSQDTS -> ACPVTHV (in Ref. 3; AAH35795)"
FT /evidence="ECO:0000305"
FT CONFLICT 1240..1242
FT /note="TEE -> FLG (in Ref. 3; AAH27450)"
FT /evidence="ECO:0000305"
FT STRAND 95..100
FT /evidence="ECO:0007829|PDB:3S8S"
FT HELIX 107..114
FT /evidence="ECO:0007829|PDB:3S8S"
FT TURN 115..117
FT /evidence="ECO:0007829|PDB:3S8S"
FT STRAND 120..127
FT /evidence="ECO:0007829|PDB:3S8S"
FT TURN 129..131
FT /evidence="ECO:0007829|PDB:3S8S"
FT STRAND 134..144
FT /evidence="ECO:0007829|PDB:3S8S"
FT HELIX 145..155
FT /evidence="ECO:0007829|PDB:3S8S"
FT STRAND 166..169
FT /evidence="ECO:0007829|PDB:3S8S"
FT HELIX 174..184
FT /evidence="ECO:0007829|PDB:3S8S"
FT TURN 190..192
FT /evidence="ECO:0007829|PDB:3S8S"
FT HELIX 1494..1497
FT /evidence="ECO:0007829|PDB:4EWR"
SQ SEQUENCE 1707 AA; 186034 MW; 0084217B0D425050 CRC64;
MDQEGGGDGQ KAPSFQWRNY KLIVDPALDP ALRRPSQKVY RYDGVHFSVN DSKYIPVEDL
QDPRCHVRSK NRDFSLPVPK FKLDEFYIGQ IPLKEVTFAR LNDNVRETFL KDMCRKYGEV
EEVEILLHPR TRKHLGLARV LFTSTRGAKE TVKNLHLTSV MGNIIHAQLD IKGQQRMKYY
ELIVNGSYTP QTVPTGGKAL SEKFQGSGAA TETAESRRRS SSDTAAYPAG TTAVGTPGNG
TPCSQDTSFS SSRQDTPSSF GQFTPQSSQG TPYTSRGSTP YSQDSAYSSS TTSTSFKPRR
SENSYQDAFS RRHFSASSAS TTASTAIAAT TAATASSSAS SSSLSSSSSS SSSSSSSQFR
SSDANYPAYY ESWNRYQRHT SYPPRRATRE EPPGAPFAEN TAERFPPSYT SYLPPEPSRP
TDQDYRPPAS EAPPPEPPEP GGGGGGGGPS PEREEVRTSP RPASPARSGS PAPETTNESV
PFAQHSSLDS RIEMLLKEQR SKFSFLASDT EEEEENSSMV LGARDTGSEV PSGSGHGPCT
PPPAPANFED VAPTGSGEPG ATRESPKANG QNQASPCSSG DDMEISDDDR GGSPPPAPTP
PQQPPPPPPP PPPPPPYLAS LPLGYPPHQP AYLLPPRPDG PPPPEYPPPP PPPPHIYDFV
NSLELMDRLG AQWGGMPMSF QMQTQMLTRL HQLRQGKGLI AASAGPPGGA FGEAFLPFPP
PQEAAYGLPY ALYAQGQEGR GAYSREAYHL PMPMAAEPLP SSSVSGEEAR LPPREEAELA
EGKTLPTAGT VGRVLAMLVQ EMKSIMQRDL NRKMVENVAF GAFDQWWESK EEKAKPFQNA
AKQQAKEEDK EKTKLKEPGL LSLVDWAKSG GTTGIEAFAF GSGLRGALRL PSFKVKRKEP
SEISEASEEK RPRPSTPAEE DEDDPEQEKE AGEPGRPGTK PPKRDEERGK TQGKHRKSFA
LDSEGEEASQ ESSSEKDEED DEEDEEDEDR EEAVDTTKKE TEVSDGEDEE SDSSSKCSLY
ADSDGENDST SDSESSSSSS SSSSSSSSSS SSSSSSSSES SSEDEEEEER PAALPSASPP
PREVPVPTPA PVEVPVPERV AGSPVTPLPE QEASPARPAG PTEESPPSAP LRPPEPPAGP
PAPAPRPDER PSSPIPLLPP PKKRRKTVSF SAIEVVPAPE PPPATPPQAK FPGPASRKAP
RGVERTIRNL PLDHASLVKS WPEEVSRGGR SRAGGRGRLT EEEEAEPGTE VDLAVLADLA
LTPARRGLPA LPAVEDSEAT ETSDEAERPR PLLSHILLEH NYALAVKPTP PAPALRPPEP
VPAPAALFSS PADEVLEAPE VVVAEAEEPK PQQLQQQREE GEEEGEEEGE EEEEESSDSS
SSSDGEGALR RRSLRSHARR RRPPPPPPPP PPRAYEPRSE FEQMTILYDI WNSGLDSEDM
SYLRLTYERL LQQTSGADWL NDTHWVHHTI TNLTTPKRKR RPQDGPREHQ TGSARSEGYY
PISKKEKDKY LDVCPVSARQ LEGVDTQGTN RVLSERRSEQ RRLLSAIGTS AIMDSDLLKL
NQLKFRKKKL RFGRSRIHEW GLFAMEPIAA DEMVIEYVGQ NIRQMVADMR EKRYVQEGIG
SSYLFRVDHD TIIDATKCGN LARFINHCCT PNCYAKVITI ESQKKIVIYS KQPIGVDEEI
TYDYKFPLED NKIPCLCGTE SCRGSLN
