ID   RN168_HUMAN             Reviewed;         571 AA.
AC   Q8IYW5; Q8NA67; Q96NS4;
DT   11-JUL-2006, integrated into UniProtKB/Swiss-Prot.
DT   01-MAR-2003, sequence version 1.
DT   05-OCT-2010, entry version 71.
DE   RecName: Full=E3 ubiquitin-protein ligase RNF168;
DE            EC=6.3.2.-;
DE   AltName: Full=RING finger protein 168;
GN   Name=RNF168;
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 [LARGE SCALE MRNA], AND VARIANT GLN-401.
RC   TISSUE=Cerebellum, and Testis;
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   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain;
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   [3]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-411; SER-414; SER-415
RP   AND THR-421, AND MASS 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   [4]
RP   INVOLVEMENT IN RIDDLE SYNDROME, FUNCTION, CATALYTIC ACTIVITY,
RP   SUBCELLULAR LOCATION, INTERACTION WITH UBE2N, AND MUTAGENESIS OF
RP   ALA-179 AND ALA-450.
RX   PubMed=19203578; DOI=10.1016/j.cell.2008.12.042;
RA   Stewart G.S., Panier S., Townsend K., Al-Hakim A.K., Kolas N.K.,
RA   Miller E.S., Nakada S., Ylanko J., Olivarius S., Mendez M.,
RA   Oldreive C., Wildenhain J., Tagliaferro A., Pelletier L.,
RA   Taubenheim N., Durandy A., Byrd P.J., Stankovic T., Taylor A.M.R.,
RA   Durocher D.;
RT   "The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling
RT   cascade at sites of DNA damage.";
RL   Cell 136:420-434(2009).
RN   [5]
RP   FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX   PubMed=19203579; DOI=10.1016/j.cell.2008.12.041;
RA   Doil C., Mailand N., Bekker-Jensen S., Menard P., Larsen D.H.,
RA   Pepperkok R., Ellenberg J., Panier S., Durocher D., Bartek J.,
RA   Lukas J., Lukas C.;
RT   "RNF168 binds and amplifies ubiquitin conjugates on damaged
RT   chromosomes to allow accumulation of repair proteins.";
RL   Cell 136:435-446(2009).
RN   [6]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-411; SER-414 AND
RP   SER-415, AND MASS SPECTROMETRY.
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).
CC   -!- FUNCTION: E3 ubiquitin-protein ligase required for accumulation of
CC       repair proteins to sites of DNA damage. Acts with UBE2N/UBC13 to
CC       amplify the RNF8-dependent histone ubiquitination. Recruited to
CC       sites of DNA damage at double-strand breaks (DSBs) by binding to
CC       ubiquitinated histone H2A and ubiquitinates histone H2A and H2AX,
CC       leading to amplify the RNF8-dependent H2A ubiquitination and
CC       promoting the formation of 'Lys-63'-linked ubiquitin conjugates.
CC       This leads to concentrate ubiquitinated histones H2A and H2AX at
CC       DNA lesions to the threshold required for recruitment of TP53BP1
CC       and BRCA1.
CC   -!- PATHWAY: Protein modification; protein ubiquitination.
CC   -!- SUBUNIT: Interacts with UBE2N/UBC13.
CC   -!- INTERACTION:
CC       P62988:RPS27A; NbExp=1; IntAct=EBI-914207, EBI-413034;
CC       P61088:UBE2N; NbExp=2; IntAct=EBI-914207, EBI-1052908;
CC   -!- SUBCELLULAR LOCATION: Nucleus. Note=Localizes to sites of DNA
CC       damage.
CC   -!- DOMAIN: The MIU motifs (motif interacting with ubiquitin) mediate
CC       the interaction with ubiquitin and the localization at sites of
CC       DNA damage.
CC   -!- DISEASE: Defects in RNF168 are the cause of Riddle syndrome
CC       [MIM:611943]. Riddle syndrome is characterized by increased
CC       radiosensitivity, immunodeficiency, mild motor control and
CC       learning difficulties, facial dysmorphism, and short stature.
CC       Defects are probably due to impaired localization of TP53BP1 and
CC       BRCA1 at DNA lesions.
CC   -!- SIMILARITY: Belongs to the RNF168 family.
CC   -!- SIMILARITY: Contains 1 RING-type zinc finger.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=BAB70801.1; Type=Erroneous initiation;
CC       Sequence=BAC04060.1; Type=Erroneous initiation;
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DR   EMBL; AK054732; BAB70801.1; ALT_INIT; mRNA.
DR   EMBL; AK093113; BAC04060.1; ALT_INIT; mRNA.
DR   EMBL; BC033791; AAH33791.1; -; mRNA.
DR   IPI; IPI00217899; -.
DR   RefSeq; NP_689830.2; -.
DR   UniGene; Hs.660132; -.
DR   PDB; 3L11; X-ray; 2.12 A; A=1-113.
DR   PDBsum; 3L11; -.
DR   ProteinModelPortal; Q8IYW5; -.
DR   SMR; Q8IYW5; 12-89.
DR   IntAct; Q8IYW5; 8.
DR   MINT; MINT-1180501; -.
DR   STRING; Q8IYW5; -.
DR   PhosphoSite; Q8IYW5; -.
DR   PRIDE; Q8IYW5; -.
DR   Ensembl; ENST00000318037; ENSP00000320898; ENSG00000163961.
DR   GeneID; 165918; -.
DR   KEGG; hsa:165918; -.
DR   UCSC; uc003fwq.1; human.
DR   CTD; 165918; -.
DR   GeneCards; GC03M196195; -.
DR   HGNC; HGNC:26661; RNF168.
DR   MIM; 611943; phenotype.
DR   MIM; 612688; gene.
DR   PharmGKB; PA134945219; -.
DR   eggNOG; prNOG07806; -.
DR   HOGENOM; HBG282499; -.
DR   HOVERGEN; HBG067220; -.
DR   InParanoid; Q8IYW5; -.
DR   OMA; KSIFQMF; -.
DR   OrthoDB; EOG99S8S3; -.
DR   PhylomeDB; Q8IYW5; -.
DR   NextBio; 88572; -.
DR   ArrayExpress; Q8IYW5; -.
DR   Bgee; Q8IYW5; -.
DR   CleanEx; HS_RNF168; -.
DR   Genevestigator; Q8IYW5; -.
DR   GermOnline; ENSG00000163961; Homo sapiens.
DR   GO; GO:0005694; C:chromosome; IEA:UniProtKB-KW.
DR   GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR   GO; GO:0000151; C:ubiquitin ligase complex; IDA:UniProtKB.
DR   GO; GO:0003682; F:chromatin binding; IDA:UniProtKB.
DR   GO; GO:0042393; F:histone binding; IDA:UniProtKB.
DR   GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB.
DR   GO; GO:0004842; F:ubiquitin-protein ligase activity; IDA:UniProtKB.
DR   GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR   GO; GO:0006302; P:double-strand break repair; IDA:UniProtKB.
DR   GO; GO:0070535; P:histone H2A K63-linked ubiquitination; IDA:UniProtKB.
DR   GO; GO:0045739; P:positive regulation of DNA repair; IDA:UniProtKB.
DR   GO; GO:0010212; P:response to ionizing radiation; IDA:UniProtKB.
DR   InterPro; IPR018957; Znf_C3HC4_RING-type.
DR   InterPro; IPR001841; Znf_RING.
DR   Pfam; PF00097; zf-C3HC4; 1.
DR   SMART; SM00184; RING; 1.
DR   PROSITE; PS00518; ZF_RING_1; FALSE_NEG.
DR   PROSITE; PS50089; ZF_RING_2; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Chromatin regulator; Complete proteome; DNA damage;
KW   DNA repair; Ligase; Metal-binding; Nucleus; Phosphoprotein;
KW   Polymorphism; Ubl conjugation pathway; Zinc; Zinc-finger.
FT   CHAIN         1    571       E3 ubiquitin-protein ligase RNF168.
FT                                /FTId=PRO_0000245596.
FT   ZN_FING      16     55       RING-type.
FT   MOTIF       168    191       MIU motif 1.
FT   MOTIF       439    462       MIU motif 2.
FT   COMPBIAS    115    177       Glu-rich.
FT   MOD_RES     411    411       Phosphoserine.
FT   MOD_RES     414    414       Phosphoserine.
FT   MOD_RES     415    415       Phosphoserine.
FT   MOD_RES     421    421       Phosphothreonine.
FT   VARIANT     387    387       K -> R (in dbSNP:rs35774921).
FT                                /FTId=VAR_034466.
FT   VARIANT     401    401       P -> Q (in dbSNP:rs3796129).
FT                                /FTId=VAR_026997.
FT   VARIANT     413    413       E -> K (in dbSNP:rs6790173).
FT                                /FTId=VAR_052110.
FT   MUTAGEN     179    179       A->G: Impairs ability to form foci
FT                                following ionizing radiation; when
FT                                associated with G-450.
FT   MUTAGEN     450    450       A->G: Impairs ability to form foci
FT                                following ionizing radiation; when
FT                                associated with G-179.
FT   CONFLICT      9      9       P -> L (in Ref. 1; BAB70801).
SQ   SEQUENCE   571 AA;  65020 MW;  51E16DA92BA654C1 CRC64;
     MALPKDAIPS LSECQCGICM EILVEPVTLP CNHTLCKPCF QSTVEKASLC CPFCRRRVSS
     WTRYHTRRNS LVNVELWTII QKHYPRECKL RASGQESEEV ADDYQPVRLL SKPGELRREY
     EEEISKVAAE RRASEEEENK ASEEYIQRLL AEEEEEEKRQ AEKRRRAMEE QLKSDEELAR
     KLSIDINNFC EGSISASPLN SRKSDPVTPK SEKKSKNKQR NTGDIQKYLT PKSQFGSASH
     SEAVQEVRKD SVSKDIDSSD RKSPTGQDTE IEDMPTLSPQ ISLGVGEQGA DSSIESPMPW
     LCACGAEWYH EGNVKTRPSN HGKELCVLSH ERPKTRVPYS KETAVMPCGR TESGCAPTSG
     VTQTNGNNTG ETENEESCLL ISKEISKRKN QESSFEAVKD PCFSAKRRKV SPESSPDQEE
     TEINFTQKLI DLEHLLFERH KQEEQDRLLA LQLQKEVDKE QMVPNRQKGS PDEYHLRATS
     SPPDKVLNGQ RKNPKDGNFK RQTHTKHPTP ERGSRDKNRQ VSLKMQLKQS VNRRKMPNST
     RDHCKVSKSA HSLQPSISQK SVFQMFQRCT K
//