ID SETD8_HUMAN Reviewed; 393 AA. AC Q9NQR1; A8K9D0; Q86W83; Q8TD09; DT 15-NOV-2002, integrated into UniProtKB/Swiss-Prot. DT 15-NOV-2002, sequence version 3. DT 05-OCT-2010, entry version 94. DE RecName: Full=Histone-lysine N-methyltransferase SETD8; DE EC=2.1.1.43; DE AltName: Full=H4-K20-HMTase SETD8; DE AltName: Full=Lysine N-methyltransferase 5A; DE AltName: Full=PR/SET domain-containing protein 07; DE Short=PR-Set7; DE Short=PR/SET07; DE AltName: Full=SET domain-containing protein 8; GN Name=SETD8; Synonyms=KMT5A, PRSET7, SET07, SET8; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 108-131; RP 220-231 AND 349-393, CHARACTERIZATION, AND MUTAGENESIS OF ARG-336. RC TISSUE=Cervix carcinoma; RX MEDLINE=22082172; PubMed=12086618; DOI=10.1016/S1097-2765(02)00548-8; RA Nishioka K., Rice J.C., Sarma K., Erdjument-Bromage H., Werner J., RA Wang Y., Chuikov S., Valenzuela P., Tempst P., Steward R., Lis J.T., RA Allis C.D., Reinberg D.; RT "PR-Set7 is a nucleosome-specific methyltransferase that modifies RT lysine 20 of histone H4 and is associated with silent chromatin."; RL Mol. Cell 9:1201-1213(2002). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), PROTEIN SEQUENCE OF 83-103; RP 109-134; 141-151; 162-172; 221-230; 245-260; 280-297 AND 350-393, RP CHARACTERIZATION, AND MUTAGENESIS OF HIS-340 AND 385-ILE--HIS-393. RX MEDLINE=22117191; PubMed=12121615; DOI=10.1016/S0960-9822(02)00924-7; RA Fang J., Feng Q., Ketel C.S., Wang H., Cao R., Xia L., RA Erdjument-Bromage H., Tempst P., Simon J.A., Zhang Y.; RT "Purification and functional characterization of SET8, a nucleosomal RT histone H4-lysine 20-specific methyltransferase."; RL Curr. Biol. 12:1086-1099(2002). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Tain F., Huang S.; RT "A novel PR/SET domain-containing gene, SET07, as a candidate tumor RT suppressor."; RL Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Thymus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Testis; 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP SUBCELLULAR LOCATION, AND DEVELOPMENTAL STAGE. RX PubMed=12208845; DOI=10.1101/gad.1014902; RA Rice J.C., Nishioka K., Sarma K., Steward R., Reinberg D., Allis C.D.; RT "Mitotic-specific methylation of histone H4 Lys 20 follows increased RT PR-Set7 expression and its localization to mitotic chromosomes."; RL Genes Dev. 16:2225-2230(2002). RN [7] RP FUNCTION, AND INDUCTION. RX PubMed=15200950; DOI=10.1016/j.molcel.2004.06.008; RA Julien E., Herr W.; RT "A switch in mitotic histone H4 lysine 20 methylation status is linked RT to M phase defects upon loss of HCF-1."; RL Mol. Cell 14:713-725(2004). RN [8] RP CATALYTIC ACTIVITY. RX PubMed=15964846; DOI=10.1074/jbc.M501691200; RA Yin Y., Liu C., Tsai S.N., Zhou B., Ngai S.M., Zhu G.; RT "SET8 recognizes the sequence RHRK20VLRDN within the N terminus of RT histone H4 and mono-methylates lysine 20."; RL J. Biol. Chem. 280:30025-30031(2005). RN [9] RP FUNCTION. RX PubMed=16517599; DOI=10.1074/jbc.M513462200; RA Sims J.K., Houston S.I., Magazinnik T., Rice J.C.; RT "A trans-tail histone code defined by monomethylated H4 Lys-20 and H3 RT Lys-9 demarcates distinct regions of silent chromatin."; RL J. Biol. Chem. 281:12760-12766(2006). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-100, AND MASS RP SPECTROMETRY. 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 X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 233-393 IN COMPLEX WITH RP HISTONE H4 AND S-ADENOSYLMETHIONINE, AND FUNCTION. RX PubMed=15933069; DOI=10.1101/gad.1315905; RA Xiao B., Jing C., Kelly G., Walker P.A., Muskett F.W., Frenkiel T.A., RA Martin S.R., Sarma K., Reinberg D., Gamblin S.J., Wilson J.R.; RT "Specificity and mechanism of the histone methyltransferase Pr-Set7."; RL Genes Dev. 19:1444-1454(2005). RN [12] RP X-RAY CRYSTALLOGRAPHY (1.45 ANGSTROMS) OF 231-393 IN COMPLEX WITH RP HISTONE H4 AND S-ADENOSYLMETHIONINE, FUNCTION, AND MUTAGENESIS OF RP TYR-286; GLU-300; CYS-311; TYR-375; ASP-379 AND HIS-388. RX PubMed=15933070; DOI=10.1101/gad.1318405; RA Couture J.-F., Collazo E., Brunzelle J.S., Trievel R.C.; RT "Structural and functional analysis of SET8, a histone H4 'Lys-20' RT methyltransferase."; RL Genes Dev. 19:1455-1465(2005). CC -!- FUNCTION: Histone methyltransferase that specifically CC monomethylates 'Lys-20' of histone H4. H4 'Lys-20' monomethylation CC is enriched during mitosis and represents a specific tag for CC epigenetic transcriptional repression. Mainly functions in CC euchromatin regions, thereby playing a central role in the CC silencing of euchromatic genes. Required for cell proliferation, CC probably by contributing to the maintenance of proper higher order CC structure of DNA during mitosis. Involved in chromosome CC condensation and proper cytokinesis. Nucleosomes are preferred as CC substrate compared to free histones. CC -!- CATALYTIC ACTIVITY: S-adenosyl-L-methionine + L-lysine-[histone] = CC S-adenosyl-L-homocysteine + N(6)-methyl-L-lysine-[histone]. CC -!- INTERACTION: CC P62805:HIST1H4A; NbExp=4; IntAct=EBI-1268946, EBI-302023; CC -!- SUBCELLULAR LOCATION: Nucleus. Chromosome. Note=Specifically CC localizes to mitotic chromosomes. Associates with silent chromatin CC on euchromatic arms. Not associated with constitutive CC heterochromatin. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q9NQR1-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9NQR1-2; Sequence=VSP_002226, VSP_002227; CC -!- DEVELOPMENTAL STAGE: Not detected during G1 phase. First detected CC during S through G2 phases, and peaks during mitosis (at protein CC level). CC -!- INDUCTION: By HCFC1 C-terminal chain, independently of HCFC1 N- CC terminal chain. CC -!- DOMAIN: Although the SET domain contains the active site of CC enzymatic activity, both sequences upstream and downstream of the CC SET domain are required for methyltransferase activity. CC -!- SIMILARITY: Belongs to the histone-lysine methyltransferase CC family. PR/SET subfamily. CC -!- SIMILARITY: Contains 1 SET domain. CC -!- CAUTION: It is uncertain whether Met-1 or Met-72 is the initiator. CC -!- SEQUENCE CAUTION: CC Sequence=AAL40879.1; Type=Erroneous initiation; CC ----------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution-NoDerivs License CC ----------------------------------------------------------------------- DR EMBL; AY064546; AAL40879.1; ALT_INIT; mRNA. DR EMBL; AY102937; AAM47033.1; -; mRNA. DR EMBL; AF287261; AAF97812.2; -; mRNA. DR EMBL; AK292645; BAF85334.1; -; mRNA. DR EMBL; BC050346; AAH50346.1; -; mRNA. DR IPI; IPI00288890; -. DR IPI; IPI00375894; -. DR RefSeq; NP_065115.3; -. DR UniGene; Hs.443735; -. DR UniGene; Hs.572262; -. DR PDB; 1ZKK; X-ray; 1.45 A; A/B/C/D=231-393. DR PDB; 2BQZ; X-ray; 1.50 A; A/E=233-393. DR PDB; 3F9W; X-ray; 1.60 A; A/B/C/D=232-393. DR PDB; 3F9X; X-ray; 1.25 A; A/B/C/D=232-393. DR PDB; 3F9Y; X-ray; 1.50 A; A/B=232-393. DR PDB; 3F9Z; X-ray; 1.60 A; A/B/C/D=232-393. DR PDBsum; 1ZKK; -. DR PDBsum; 2BQZ; -. DR PDBsum; 3F9W; -. DR PDBsum; 3F9X; -. DR PDBsum; 3F9Y; -. DR PDBsum; 3F9Z; -. DR ProteinModelPortal; Q9NQR1; -. DR IntAct; Q9NQR1; 4. DR STRING; Q9NQR1; -. DR PhosphoSite; Q9NQR1; -. DR PRIDE; Q9NQR1; -. DR Ensembl; ENST00000330479; ENSP00000332995; ENSG00000183955. DR Ensembl; ENST00000402868; ENSP00000384629; ENSG00000183955. DR GeneID; 387893; -. DR KEGG; hsa:387893; -. DR UCSC; uc001uew.1; human. DR CTD; 387893; -. DR GeneCards; GC12P123868; -. DR H-InvDB; HIX0037637; -. DR HGNC; HGNC:29489; SETD8. DR MIM; 607240; gene. DR eggNOG; prNOG16701; -. DR HOGENOM; HBG388866; -. DR HOVERGEN; HBG067546; -. DR InParanoid; Q9NQR1; -. DR OMA; FSRGEFV; -. DR BRENDA; 2.1.1.43; 247. DR NextBio; 101711; -. DR ArrayExpress; Q9NQR1; -. DR Bgee; Q9NQR1; -. DR CleanEx; HS_SETD8; -. DR Genevestigator; Q9NQR1; -. DR GO; GO:0005694; C:chromosome; IEA:UniProtKB-KW. DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell. DR GO; GO:0018024; F:histone-lysine N-methyltransferase activity; IEA:EC. DR GO; GO:0003714; F:transcription corepressor activity; IDA:UniProtKB. DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW. DR GO; GO:0007067; P:mitosis; IEA:UniProtKB-KW. DR GO; GO:0006350; P:transcription; IEA:UniProtKB-KW. DR InterPro; IPR016858; Hist_H4-K20_MeTrfase. DR InterPro; IPR001214; SET_dom. DR Pfam; PF00856; SET; 1. DR PIRSF; PIRSF027717; Histone_H4-K20_mtfrase; 1. DR SMART; SM00317; SET; 1. DR PROSITE; PS50280; SET; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell cycle; Cell division; KW Chromatin regulator; Chromosome; Coiled coil; Complete proteome; KW Direct protein sequencing; Methyltransferase; Mitosis; Nucleus; KW Phosphoprotein; Repressor; S-adenosyl-L-methionine; Transcription; KW Transcription regulation; Transferase. FT CHAIN 1 393 Histone-lysine N-methyltransferase SETD8. FT /FTId=PRO_0000186081. FT DOMAIN 256 382 SET. FT REGION 267 269 S-adenosyl-L-methionine binding. FT REGION 339 340 S-adenosyl-L-methionine binding. FT COILED 134 163 Potential. FT COMPBIAS 6 67 Ala-rich. FT COMPBIAS 29 32 Poly-Arg. FT BINDING 312 312 S-adenosyl-L-methionine. FT MOD_RES 100 100 Phosphoserine. FT VAR_SEQ 1 41 Missing (in isoform 2). FT /FTId=VSP_002226. FT VAR_SEQ 42 57 PGRAAGGKMSKPCAVE -> MARGRKMSKPRAVEAA (in FT isoform 2). FT /FTId=VSP_002227. FT MUTAGEN 286 286 Y->A,F: Strongly reduces affinity for FT histone H4 and abolishes FT methyltransferase activity. FT MUTAGEN 300 300 E->A: Strongly reduces affinity for FT histone H4. FT MUTAGEN 311 311 C->A: Strongly reduces affinity for FT histone H4. FT MUTAGEN 336 336 R->G: Abolishes methyltransferase FT activity. FT MUTAGEN 340 340 H->A: Strongly decreases FT methyltransferase activity. FT MUTAGEN 375 375 Y->A: Strongly reduces affinity for FT histone H4 and methyltransferase FT activity. FT MUTAGEN 375 375 Y->F: Alters methyltransferase activity, FT so that both monomethylation and FT dimethylation take place. FT MUTAGEN 379 379 D->A,N: Abolishes histone H4 binding and FT methyltransferase activity. FT MUTAGEN 385 393 Missing: Abolishes methyltransferase FT activity. FT MUTAGEN 388 388 H->A,E: Strongly reduces affinity for FT histone H4. FT MUTAGEN 388 388 H->F: Increases affinity for histone H4. FT CONFLICT 162 163 KG -> RR (in Ref. 3; AAF97812). FT CONFLICT 281 281 D -> A (in Ref. 3; AAF97812). FT CONFLICT 343 343 C -> R (in Ref. 3; AAF97812). FT CONFLICT 357 357 P -> R (in Ref. 5; AAH50346). FT CONFLICT 373 373 L -> P (in Ref. 3; AAF97812). FT HELIX 236 253 FT STRAND 259 264 FT TURN 265 267 FT STRAND 268 275 FT STRAND 282 286 FT STRAND 288 292 FT HELIX 293 303 FT STRAND 313 318 FT STRAND 321 326 FT HELIX 335 337 FT STRAND 345 353 FT STRAND 356 365 FT HELIX 382 387 FT HELIX 389 392 SQ SEQUENCE 393 AA; 42890 MW; 2DCD9B697834B5BD CRC64; MGEGGAAAAL VAAAAAAAAA AAAVVAGQRR RRLGRRARCH GPGRAAGGKM SKPCAVEAAA AAVAATAPGP EMVERRGPGR PRTDGENVFT GQSKIYSYMS PNKCSGMRFP LQEENSVTHH EVKCQGKPLA GIYRKREEKR NAGNAVRSAM KSEEQKIKDA RKGPLVPFPN QKSEAAEPPK TPPSSCDSTN AAIAKQALKK PIKGKQAPRK KAQGKTQQNR KLTDFYPVRR SSRKSKAELQ SEERKRIDEL IESGKEEGMK IDLIDGKGRG VIATKQFSRG DFVVEYHGDL IEITDAKKRE ALYAQDPSTG CYMYYFQYLS KTYCVDATRE TNRLGRLINH SKCGNCQTKL HDIDGVPHLI LIASRDIAAG EELLYDYGDR SKASIEAHPW LKH //