ID A0A2K5HSS4_COLAP Unreviewed; 486 AA. AC A0A2K5HSS4; DT 28-MAR-2018, integrated into UniProtKB/TrEMBL. DT 28-MAR-2018, sequence version 1. DT 05-JUN-2019, entry version 10. DE RecName: Full=E3 ubiquitin-protein ligase RNF8 {ECO:0000256|HAMAP-Rule:MF_03067, ECO:0000256|PIRNR:PIRNR037950}; DE EC=2.3.2.27 {ECO:0000256|HAMAP-Rule:MF_03067, ECO:0000256|PIRNR:PIRNR037950}; DE AltName: Full=RING finger protein 8 {ECO:0000256|HAMAP-Rule:MF_03067}; DE AltName: Full=RING-type E3 ubiquitin transferase RNF8 {ECO:0000256|HAMAP-Rule:MF_03067}; GN Name=RNF8 {ECO:0000256|HAMAP-Rule:MF_03067, GN ECO:0000313|Ensembl:ENSCANP00000007391}; OS Colobus angolensis palliatus (Peters' Angolan colobus). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Cercopithecidae; Colobinae; Colobus. OX NCBI_TaxID=336983 {ECO:0000313|Ensembl:ENSCANP00000007391, ECO:0000313|Proteomes:UP000233080}; RN [1] {ECO:0000313|Ensembl:ENSCANP00000007391, ECO:0000313|Proteomes:UP000233080} RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Hughes D.S., Murali S., Raveendran M., Korchina V., Bandaranaike D., RA Bellair M., Blankenburg K., Chao H., Dahdouli M., Dinh H., RA Doddapaneni H., Gnanaolivu R., Gross S., Jayaseelan J., Jones J., RA Khan Z., Kovar C., Kurapati P., Le B., Lee S., Mathew T., RA Narasimhan A., Okwuonu G., Ongeri F., Osuji N., Qu C., Quiroz J., RA Rajbhandari K., Reid J.G., Santibanez J., Skinner E., Wang Y., Xin Y., RA Han Y., Muzny D.M., Richards S., Worley K.C., Rogers J., Gibbs R.A.; RT "Black and white colobus reference genome project."; RL Submitted (FEB-2015) to the EMBL/GenBank/DDBJ databases. RN [2] {ECO:0000313|Ensembl:ENSCANP00000007391} RP IDENTIFICATION. RG Ensembl; RL Submitted (FEB-2018) to UniProtKB. CC -!- FUNCTION: E3 ubiquitin-protein ligase that plays a key role in DNA CC damage signaling via 2 distinct roles: by mediating the 'Lys-63'- CC linked ubiquitination of histones H2A and H2AX and promoting the CC recruitment of DNA repair proteins at double-strand breaks (DSBs) CC sites, and by catalyzing 'Lys-48'-linked ubiquitination to remove CC target proteins from DNA damage sites. Following DNA DSBs, it is CC recruited to the sites of damage by ATM-phosphorylated MDC1 and CC catalyzes the 'Lys-63'-linked ubiquitination of histones H2A and CC H2AX, thereby promoting the formation of TP53BP1 and BRCA1 CC ionizing radiation-induced foci (IRIF). Also controls the CC recruitment of UIMC1-BRCC3 (RAP80-BRCC36) and PAXIP1/PTIP to DNA CC damage sites. Also recruited at DNA interstrand cross-links (ICLs) CC sites and catalyzes 'Lys-63'-linked ubiquitination of histones H2A CC and H2AX, leading to recruitment of FAAP20 and Fanconi anemia (FA) CC complex, followed by interstrand cross-link repair. H2A CC ubiquitination also mediates the ATM-dependent transcriptional CC silencing at regions flanking DSBs in cis, a mechanism to avoid CC collision between transcription and repair intermediates. Promotes CC the formation of 'Lys-63'-linked polyubiquitin chains via CC interactions with the specific ubiquitin-conjugating UBE2N/UBC13 CC and ubiquitinates non-histone substrates such as PCNA. Substrates CC that are polyubiquitinated at 'Lys-63' are usually not targeted CC for degradation. Also catalyzes the formation of 'Lys-48'-linked CC polyubiquitin chains via interaction with the ubiquitin- CC conjugating UBE2L6/UBCH8, leading to degradation of substrate CC proteins such as CHEK2, JMJD2A/KDM4A and KU80/XRCC5: it is still CC unclear how the preference toward 'Lys-48'- versus 'Lys-63'-linked CC ubiquitination is regulated but it could be due to RNF8 ability to CC interact with specific E2 specific ligases. For instance, CC interaction with phosphorylated HERC2 promotes the association CC between RNF8 and UBE2N/UBC13 and favors the specific formation of CC 'Lys-63'-linked ubiquitin chains. Promotes non-homologous end CC joining (NHEJ) by promoting the 'Lys-48'-linked ubiquitination and CC degradation the of KU80/XRCC5. Following DNA damage, mediates the CC ubiquitination and degradation of JMJD2A/KDM4A in collaboration CC with RNF168, leading to unmask H4K20me2 mark and promote the CC recruitment of TP53BP1 at DNA damage sites. Following DNA damage, CC mediates the ubiquitination and degradation of POLD4/p12, a CC subunit of DNA polymerase delta. In the absence of POLD4, DNA CC polymerase delta complex exhibits higher proofreading activity. In CC addition to its function in damage signaling, also plays a role in CC higher-order chromatin structure by mediating extensive chromatin CC decondensation. Involved in the activation of ATM by promoting CC histone H2B ubiquitination, which indirectly triggers histone H4 CC 'Lys-16' acetylation (H4K16ac), establishing a chromatin CC environment that promotes efficient activation of ATM kinase. CC Required in the testis, where it plays a role in the replacement CC of histones during spermatogenesis. At uncapped telomeres, CC promotes the joining of deprotected chromosome ends by inducing CC H2A ubiquitination and TP53BP1 recruitment, suggesting that it may CC enhance cancer development by aggravating telomere-induced genome CC instability in case of telomeric crisis. Promotes the assembly of CC RAD51 at DNA DSBs in the absence of BRCA1 and TP53BP1 Also CC involved in class switch recombination in immune system, via its CC role in regulation of DSBs repair. May be required for proper exit CC from mitosis after spindle checkpoint activation and may regulate CC cytokinesis. May play a role in the regulation of RXRA-mediated CC transcriptional activity. Not involved in RXRA ubiquitination by CC UBE2E2. {ECO:0000256|HAMAP-Rule:MF_03067}. CC -!- CATALYTIC ACTIVITY: CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L- CC cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin- CC conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor CC protein]-L-lysine.; EC=2.3.2.27; Evidence={ECO:0000256|HAMAP- CC Rule:MF_03067}; CC -!- PATHWAY: Protein modification; protein ubiquitination. CC {ECO:0000256|HAMAP-Rule:MF_03067, ECO:0000256|PIRNR:PIRNR037950}. CC -!- SUBUNIT: Homodimer. Forms a E2-E3 ubiquitin ligase complex CC composed of the RNF8 homodimer and a E2 heterodimer of UBE2N and CC UBE2V2. Interacts with class III E2s, including UBE2E1, UBE2E2, CC and UBE2E3 and with UBE2N. Interacts with RXRA. Interacts (via FHA CC domain) with phosphorylated HERC2 (via C-terminus). Interacts with CC PIWIL1; leading to sequester RNF8 in the cytoplasm. CC {ECO:0000256|HAMAP-Rule:MF_03067}. CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000256|HAMAP-Rule:MF_03067}. CC Cytoplasm {ECO:0000256|HAMAP-Rule:MF_03067}. Midbody CC {ECO:0000256|HAMAP-Rule:MF_03067}. Chromosome, telomere CC {ECO:0000256|HAMAP-Rule:MF_03067}. Note=Recruited at uncapped CC telomeres. Following DNA double-strand breaks, recruited to the CC sites of damage. During prophase, concomitant with nuclear CC envelope breakdown, localizes throughout the cell, with a dotted CC pattern. In telophase, again in the nucleus and also with a CC discrete dotted pattern in the cytoplasm. In late telophase and CC during cytokinesis, localizes in the midbody of the tubulin bridge CC joining the daughter cells. Does not seem to be associated with CC condensed chromosomes at any time during the cell cycle. During CC spermatogenesis, sequestered in the cytoplasm by PIWIL1: RNF8 is CC released following ubiquitination and degradation of PIWIL1. CC {ECO:0000256|HAMAP-Rule:MF_03067}. CC -!- DOMAIN: The FHA domain specifically recognizes and binds ATM- CC phosphorylated MDC1 and phosphorylated HERC2. {ECO:0000256|HAMAP- CC Rule:MF_03067}. CC -!- PTM: Autoubiquitinated through 'Lys-48' and 'Lys-63' of ubiquitin. CC 'Lys-63' polyubiquitination is mediated by UBE2N. 'Lys-29'-type CC polyubiquitination is also observed, but it doesn't require its CC own functional RING-type zinc finger. {ECO:0000256|HAMAP- CC Rule:MF_03067}. CC -!- SIMILARITY: Belongs to the RNF8 family. {ECO:0000256|HAMAP- CC Rule:MF_03067, ECO:0000256|PIRNR:PIRNR037950}. CC -!- CAUTION: According to a well-established model, RNF8 initiate H2A CC 'Lys-63'-linked ubiquitination leading to recruitment of RNF168 to CC amplify H2A 'Lys-63'-linked ubiquitination. However, other data CC suggest that RNF168 is the priming ubiquitin ligase by mediating CC monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal histone CC H2A (H2AK13Ub and H2AK15Ub respectively). These data suggest that CC RNF168 might be recruited to DSBs sites in a RNF8-dependent manner CC by binding to non-histone proteins ubiquitinated via 'Lys-63'- CC linked and initiates monoubiquitination of H2A, which is then CC amplified by RNF8. Additional evidences are however required to CC confirm these data. {ECO:0000256|HAMAP-Rule:MF_03067}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR RefSeq; XP_011799916.1; XM_011944526.1. DR Ensembl; ENSCANT00000027385; ENSCANP00000007391; ENSCANG00000024187. DR GeneID; 105513611; -. DR CTD; 9025; -. DR GeneTree; ENSGT00400000022349; -. DR OrthoDB; 1585372at2759; -. DR UniPathway; UPA00143; -. DR Proteomes; UP000233080; Whole Genome Shotgun Assembly. DR GO; GO:0000781; C:chromosome, telomeric region; IEA:UniProtKB-SubCell. DR GO; GO:0005829; C:cytosol; IEA:Ensembl. DR GO; GO:0030496; C:midbody; IEA:UniProtKB-SubCell. DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell. DR GO; GO:0035861; C:site of double-strand break; IEA:Ensembl. DR GO; GO:0000151; C:ubiquitin ligase complex; IEA:UniProtKB-UniRule. DR GO; GO:0003682; F:chromatin binding; IEA:UniProtKB-UniRule. DR GO; GO:0042393; F:histone binding; IEA:UniProtKB-UniRule. DR GO; GO:0042803; F:protein homodimerization activity; IEA:UniProtKB-UniRule. DR GO; GO:0043130; F:ubiquitin binding; IEA:UniProtKB-UniRule. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IEA:Ensembl. DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IEA:UniProtKB-UniRule. DR GO; GO:0008270; F:zinc ion binding; IEA:Ensembl. DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW. DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW. DR GO; GO:0006302; P:double-strand break repair; IEA:UniProtKB-UniRule. DR GO; GO:0070535; P:histone H2A K63-linked ubiquitination; IEA:Ensembl. DR GO; GO:0033523; P:histone H2B ubiquitination; IEA:UniProtKB-UniRule. DR GO; GO:0034244; P:negative regulation of transcription elongation from RNA polymerase II promoter; IEA:Ensembl. DR GO; GO:0045739; P:positive regulation of DNA repair; IEA:UniProtKB-UniRule. DR GO; GO:0051865; P:protein autoubiquitination; IEA:Ensembl. DR GO; GO:0070936; P:protein K48-linked ubiquitination; IEA:Ensembl. DR GO; GO:0010212; P:response to ionizing radiation; IEA:UniProtKB-UniRule. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IEA:Ensembl. DR CDD; cd00060; FHA; 1. DR Gene3D; 3.30.40.10; -; 1. DR HAMAP; MF_03067; RNF8; 1. DR InterPro; IPR000253; FHA_dom. DR InterPro; IPR017335; RNF8. DR InterPro; IPR008984; SMAD_FHA_dom_sf. DR InterPro; IPR001841; Znf_RING. DR InterPro; IPR013083; Znf_RING/FYVE/PHD. DR InterPro; IPR017907; Znf_RING_CS. DR Pfam; PF00498; FHA; 1. DR PIRSF; PIRSF037950; E3_ubiquit_lig_RNF8; 1. DR SMART; SM00240; FHA; 1. DR SMART; SM00184; RING; 1. DR SUPFAM; SSF49879; SSF49879; 1. DR PROSITE; PS50006; FHA_DOMAIN; 1. DR PROSITE; PS00518; ZF_RING_1; 1. DR PROSITE; PS50089; ZF_RING_2; 1. PE 3: Inferred from homology; KW Cell cycle {ECO:0000256|HAMAP-Rule:MF_03067}; KW Cell division {ECO:0000256|HAMAP-Rule:MF_03067}; KW Chromatin regulator {ECO:0000256|HAMAP-Rule:MF_03067, KW ECO:0000256|PIRNR:PIRNR037950}; KW Chromosome {ECO:0000256|HAMAP-Rule:MF_03067}; KW Coiled coil {ECO:0000256|SAM:Coils}; KW Complete proteome {ECO:0000313|Proteomes:UP000233080}; KW Cytoplasm {ECO:0000256|HAMAP-Rule:MF_03067}; KW DNA damage {ECO:0000256|HAMAP-Rule:MF_03067, KW ECO:0000256|PIRNR:PIRNR037950}; KW DNA repair {ECO:0000256|HAMAP-Rule:MF_03067, KW ECO:0000256|PIRNR:PIRNR037950}; KW Metal-binding {ECO:0000256|HAMAP-Rule:MF_03067}; KW Mitosis {ECO:0000256|HAMAP-Rule:MF_03067}; KW Nucleus {ECO:0000256|HAMAP-Rule:MF_03067, KW ECO:0000256|PIRNR:PIRNR037950}; KW Reference proteome {ECO:0000313|Proteomes:UP000233080}; KW Telomere {ECO:0000256|HAMAP-Rule:MF_03067}; KW Transferase {ECO:0000256|HAMAP-Rule:MF_03067}; KW Ubl conjugation {ECO:0000256|HAMAP-Rule:MF_03067}; KW Ubl conjugation pathway {ECO:0000256|HAMAP-Rule:MF_03067, KW ECO:0000256|PIRNR:PIRNR037950}; KW Zinc {ECO:0000256|HAMAP-Rule:MF_03067}; KW Zinc-finger {ECO:0000256|HAMAP-Rule:MF_03067, ECO:0000256|PROSITE- KW ProRule:PRU00175}. FT DOMAIN 38 92 FHA. {ECO:0000259|PROSITE:PS50006}. FT DOMAIN 404 442 RING-type. {ECO:0000259|PROSITE:PS50089}. FT REGION 68 72 Required for interaction with PIWIL1. FT {ECO:0000256|HAMAP-Rule:MF_03067}. FT REGION 182 215 Disordered. {ECO:0000256|MobiDB-lite: FT A0A2K5HSS4}. FT COILED 279 299 {ECO:0000256|SAM:Coils}. FT COILED 302 331 {ECO:0000256|SAM:Coils}. FT COILED 334 393 {ECO:0000256|SAM:Coils}. SQ SEQUENCE 486 AA; 55611 MW; 2F1FD22E84B1F59A CRC64; MGEPGFFVTG DRAGGRSWCL RRVGMSAGWL LLEDGLEVTV GRGFGVTYQL VSKICPLMIS RNHCVLKQNP EGQWTIMDNK SLNGVWLNRA RLEPLRVYSI QQGDYIQLGV PLENKENAEY EYEVTEEDWE TIYPCLSPKN DQMIEKNKEL RTKRKFSLDQ LGGPGAEGPS NLKSKINKVS YESGQSVKSQ GKGEVASTPS ENLDPKLTAL EPSKNTTGAP IYSGFPIVTE VHHEQKASNS SASQRSLQMF KVTMSRILRL KIQMQEKHEA VTNVKKQTQK GNSKKIVQME QELQDLQSQL CAEQAQQQAR VEQLEKTFQE EEQHLEGLEI AQGEEDLKQQ LAQALQEHWA LMEELNRSKK DFEAIIQAKN KELEQTKEEK EKVQAQKEEV LSHMNDVLEN ELQCIICSEY FIEAVTLNCA HSFCSYCINE WMKRKIECPI CRKDIESKTY SLVLDNCINK MVNNLSSEVK ERRIVLIRER KAKRLF //