ID:RNF8_HUMAN DESCRIPTION: RecName: Full=E3 ubiquitin-protein ligase RNF8; Short=hRNF8; EC=6.3.2.-; AltName: Full=RING finger protein 8; FUNCTION: E3 ubiquitin-protein ligase that plays a key role in DNA damage signaling via 2 distinct roles: by mediating the 'Lys-63'- linked ubiquitination of histones H2A and H2AX and promoting the recruitment of DNA repair proteins at double-strand breaks (DSBs) sites, and by catalyzing 'Lys-48'-linked ubiquitination to remove target proteins from DNA damage sites. Following DNA DSBs, it is recruited to the sites of damage by ATM-phosphorylated MDC1 and catalyzes the 'Lys-63'-linked ubiquitination of histones H2A and H2AX, thereby promoting the formation of TP53BP1 and BRCA1 ionizing radiation-induced foci (IRIF). Also controls the recruitment of UIMC1-BRCC3 (RAP80-BRCC36) and PAXIP1/PTIP to DNA damage sites. Also recruited at DNA interstrand cross-links (ICLs) sites and catalyzes 'Lys-63'-linked ubiquitination of histones H2A and H2AX, leading to recruitment of FAAP20/C1orf86 and Fanconi anemia (FA) complex, followed by interstrand cross-link repair. H2A ubiquitination also mediates the ATM-dependent transcriptional silencing at regions flanking DSBs in cis, a mechanism to avoid collision between transcription and repair intermediates. Promotes the formation of 'Lys-63'-linked polyubiquitin chains via interactions with the specific ubiquitin-conjugating UBE2N/UBC13 and ubiquitinates non-histone substrates such as PCNA. Substrates that are polyubiquitinated at 'Lys-63' are usually not targeted for degradation. Also catalyzes the formation of 'Lys-48'-linked polyubiquitin chains via interaction with the ubiquitin- conjugating UBE2L6/UBCH8, leading to degradation of substrate proteins such as CHEK2, JMJD2A/KDM4A and KU80/XRCC5: it is still unclear how the preference toward 'Lys-48'- versus 'Lys-63'-linked ubiquitination is regulated but it could be due to RNF8 ability to interact with specific E2 specific ligases. For instance, interaction with phosphorylated HERC2 promotes the association between RNF8 and UBE2N/UBC13 and favors the specific formation of 'Lys-63'-linked ubiquitin chains. Promotes non-homologous end joining (NHEJ) by promoting the 'Lys-48'-linked ubiquitination and degradation the of KU80/XRCC5. Following DNA damage, mediates the ubiquitination and degradation of JMJD2A/KDM4A in collaboration with RNF168, leading to unmask H4K20me2 mark and promote the recruitment of TP53BP1 at DNA damage sites. In addition to its function in damage signaling, also plays a role in higher-order chromatin structure by mediating extensive chromatin decondensation. Involved in the activation of ATM by promoting histone H2B ubiquitination, which indirectly triggers histone H4 'Lys-16' acetylation (H4K16ac), establishing a chromatin environment that promotes efficient activation of ATM kinase. Required in the testis, where it plays a role in the replacement of histones during spermatogenesis. At uncapped telomeres, promotes the joining of deprotected chromosome ends by inducing H2A ubiquitination and TP53BP1 recruitment, suggesting that it may enhance cancer development by aggraving telomere-induced genome instability in case of telomeric crisis. Promotes the assembly of RAD51 at DNA DSBs in the absence of BRCA1 and TP53BP1 Also involved in class switch recombination in immune system, via its role in regulation of DSBs repair. May be required for proper exit from mitosis after spindle checkpoint activation and may regulate cytokinesis. May play a role in the regulation of RXRA-mediated transcriptional activity. Not involved in RXRA ubiquitination by UBE2E2. PATHWAY: Protein modification; protein ubiquitination. SUBUNIT: Homodimer. Forms a E2-E3 ubiquitin ligase complex composed of the RNF8 homodimer and a E2 heterodimer of UBE2N and UBE2V2. Interacts with class III E2s, including UBE2E1, UBE2E2, and UBE2E3 and with UBE2N. Interacts with RXRA. Interacts (via FHA domain) with ATM-phosphorylated MDC1. Interacts (via FHA domain) with 'Thr-4827' phosphorylated HERC2 (via C-terminus). Interacts (via FHA domain) with phosphorylated human herpesvirus 1 ICP0 protein; leading to RNF8 degradation by the proteasome. INTERACTION: Q14676:MDC1; NbExp=11; IntAct=EBI-373337, EBI-495644; SUBCELLULAR LOCATION: Nucleus. Midbody. Chromosome, telomere (By similarity). Note=Recruited at uncapped telomeres (By similarity). Following DNA double-strand breaks, recruited to the sites of damage. During prophase, concomitant with nuclear envelope breakdown, localizes throughout the cell, with a dotted pattern. In telophase, again in the nucleus and also with a discrete dotted pattern in the cytoplasm. In late telophase and during cytokinesis, localizes in the midbody of the tubulin bridge joining the daughter cells. Does not seem to be associated with condensed chromosomes at any time during the cell cycle. TISSUE SPECIFICITY: Ubiquitous. In fetal tissues, highest expression in brain, thymus and liver. In adult tissues, highest levels in brain and testis, lowest levels in peripheral blood cells. DEVELOPMENTAL STAGE: Low levels at the G1-S boundary increase in intensity during S phase and until the end of the G2 phase. Abruptly decreases in late mitosis (at protein level). Barely detectable in anaphase. DOMAIN: The FHA domain specifically recognizes and binds ATM- phosphorylated MDC1 and 'Thr-4827' phosphorylated HERC2. PTM: Autoubiquitinated through 'Lys-48' and 'Lys-63' of ubiquitin. 'Lys-63' polyubiquitination is mediated by UBE2N. 'Lys-29'-type polyubiquitination is also observed, but it doesn't require its own functional RING-type zinc finger. SIMILARITY: Belongs to the RNF8 family. SIMILARITY: Contains 1 FHA domain. SIMILARITY: Contains 1 RING-type zinc finger. CAUTION: According to a well-established model, RNF8 initiate H2A 'Lys-63'-linked ubiquitination leading to recruitment of RNF168 to amplify H2A 'Lys-63'-linked ubiquitination (PubMed:19203578 and PubMed:19203579). However, other data suggest that RNF168 is the priming ubiquitin ligase by mediating monoubiquitination of 'Lys- 13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub respectively) (PubMed:22980979). These data suggest that RNF168 might be recruited to DSBs sites in a RNF8-dependent manner by binding to non-histone proteins ubiquitinated via 'Lys-63'-linked and initiates monoubiquitination of H2A, which is then amplified by RNF8 (PubMed:22980979). Additional evidences are however required to confirm these data. SEQUENCE CAUTION: Sequence=BAA31621.2; Type=Erroneous initiation; Note=Translation N-terminally extended; Sequence=BAG60572.1; Type=Erroneous translation; Note=Wrong choice of CDS; Sequence=EAX03945.1; Type=Erroneous gene model prediction;
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on O76064
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
BC007517 - Homo sapiens ring finger protein 8, mRNA (cDNA clone MGC:4554 IMAGE:3028746), complete cds. AB014546 - Homo sapiens KIAA0646 mRNA for KIAA0646 protein. AK222765 - Homo sapiens mRNA for ring finger protein 8 isoform 1 variant, clone: HEP00632. AK298319 - Homo sapiens cDNA FLJ50824 complete cds, highly similar to Ubiquitin ligase protein RNF8 (EC 6.3.2.-). AK022075 - Homo sapiens cDNA FLJ12013 fis, clone HEMBB1001673, highly similar to Homo sapiens gene for new zinc finger protein. AB383937 - Synthetic construct DNA, clone: pF1KSDA0646, Homo sapiens RNF8 gene for E3 ubiquitin-protein ligase RNF8, complete cds, without stop codon, in Flexi system. BT007446 - Homo sapiens ring finger protein (C3HC4 type) 8 mRNA, complete cds. DQ890737 - Synthetic construct clone IMAGE:100003367; FLH165572.01X; RZPDo839E01160D ring finger protein 8 (RNF8) gene, encodes complete protein. DQ893909 - Synthetic construct Homo sapiens clone IMAGE:100008369; FLH165570.01L; RZPDo839E01159D ring finger protein 8 (RNF8) gene, encodes complete protein. KJ897946 - Synthetic construct Homo sapiens clone ccsbBroadEn_07340 RNF8 gene, encodes complete protein. AF334675 - Homo sapiens UBC13/UEV-interacting ring finger protein mRNA, complete cds. AK308840 - Homo sapiens cDNA, FLJ98881. CU675685 - Synthetic construct Homo sapiens gateway clone IMAGE:100019622 5' read RNF8 mRNA. DL491940 - Novel nucleic acids. DL490499 - Novel nucleic acids. JD225825 - Sequence 206849 from Patent EP1572962. JD420945 - Sequence 401969 from Patent EP1572962. JD062852 - Sequence 43876 from Patent EP1572962. JD195322 - Sequence 176346 from Patent EP1572962. JD383624 - Sequence 364648 from Patent EP1572962. JD219269 - Sequence 200293 from Patent EP1572962. JD101214 - Sequence 82238 from Patent EP1572962. JD122784 - Sequence 103808 from Patent EP1572962. JD111809 - Sequence 92833 from Patent EP1572962. JD202302 - Sequence 183326 from Patent EP1572962. JD223500 - Sequence 204524 from Patent EP1572962. JD563223 - Sequence 544247 from Patent EP1572962. JD097287 - Sequence 78311 from Patent EP1572962. JD285694 - Sequence 266718 from Patent EP1572962. JD171183 - Sequence 152207 from Patent EP1572962. JD293072 - Sequence 274096 from Patent EP1572962. JD456469 - Sequence 437493 from Patent EP1572962. JD120982 - Sequence 102006 from Patent EP1572962. JD465926 - Sequence 446950 from Patent EP1572962. JD382332 - Sequence 363356 from Patent EP1572962. JD103403 - Sequence 84427 from Patent EP1572962. JD306806 - Sequence 287830 from Patent EP1572962. JD071961 - Sequence 52985 from Patent EP1572962. JD277015 - Sequence 258039 from Patent EP1572962. JD108097 - Sequence 89121 from Patent EP1572962. JD342183 - Sequence 323207 from Patent EP1572962. JD314992 - Sequence 296016 from Patent EP1572962. JD254766 - Sequence 235790 from Patent EP1572962. JD254767 - Sequence 235791 from Patent EP1572962. JD264843 - Sequence 245867 from Patent EP1572962. JD076020 - Sequence 57044 from Patent EP1572962. JD429605 - Sequence 410629 from Patent EP1572962. JD286100 - Sequence 267124 from Patent EP1572962. JD348901 - Sequence 329925 from Patent EP1572962. JD226052 - Sequence 207076 from Patent EP1572962. JD404237 - Sequence 385261 from Patent EP1572962. JD293759 - Sequence 274783 from Patent EP1572962. JD377513 - Sequence 358537 from Patent EP1572962. JD092070 - Sequence 73094 from Patent EP1572962. JD436170 - Sequence 417194 from Patent EP1572962. JD330031 - Sequence 311055 from Patent EP1572962. JD174419 - Sequence 155443 from Patent EP1572962. JD420385 - Sequence 401409 from Patent EP1572962. JD081088 - Sequence 62112 from Patent EP1572962. JD345069 - Sequence 326093 from Patent EP1572962. JD061299 - Sequence 42323 from Patent EP1572962. JD379140 - Sequence 360164 from Patent EP1572962. JD267269 - Sequence 248293 from Patent EP1572962. JD083461 - Sequence 64485 from Patent EP1572962. JD258169 - Sequence 239193 from Patent EP1572962. JD369455 - Sequence 350479 from Patent EP1572962. JD413550 - Sequence 394574 from Patent EP1572962. JD424156 - Sequence 405180 from Patent EP1572962. JD347495 - Sequence 328519 from Patent EP1572962. JD194086 - Sequence 175110 from Patent EP1572962. JD265410 - Sequence 246434 from Patent EP1572962. JD060340 - Sequence 41364 from Patent EP1572962. JD171681 - Sequence 152705 from Patent EP1572962. JD469684 - Sequence 450708 from Patent EP1572962. JD103548 - Sequence 84572 from Patent EP1572962. JD233236 - Sequence 214260 from Patent EP1572962. JD039158 - Sequence 20182 from Patent EP1572962. JD045539 - Sequence 26563 from Patent EP1572962. JD182151 - Sequence 163175 from Patent EP1572962. JD358158 - Sequence 339182 from Patent EP1572962. JD114569 - Sequence 95593 from Patent EP1572962. JD161190 - Sequence 142214 from Patent EP1572962. JD516714 - Sequence 497738 from Patent EP1572962.
Biochemical and Signaling Pathways
Reactome (by CSHL, EBI, and GO)
Protein O76064 (Reactome details) participates in the following event(s):
R-HSA-5682588 RNF8 binds phosphorylated MDC1 at DNA DSBs R-HSA-5684071 RNF4 ubiquitinates MDC1 R-HSA-5693599 Association of Ku heterodimer with ends of DNA double-strand break R-HSA-5682586 HERC2 and PIAS4 are recruited to DNA DSBs R-HSA-5682598 ATM phosphorylates HERC2 R-HSA-5682607 PIAS4 SUMOylates HERC2 with SUMO1 at DNA DSBs R-HSA-5682629 HERC2 facilitates UBE2N:UBE2V2 binding to RNF8 R-HSA-5682863 RNF168 binds DNA DSBs R-HSA-5683077 RNF8 and RNF168 ubiquitinate KDM4A,B R-HSA-5682858 RNF8 and RNF168 ubiquitinate H2AFX R-HSA-5693566 TP53BP1 associates with H4K20Me2 at DNA DSBs R-HSA-5683384 UIMC1 and FAM175A bind DNA DSBs R-HSA-5683405 PPP5C dephosphorylates TP53BP1 R-HSA-5683425 ATM phosphorylates TP53BP1 at DNA DSBs R-HSA-5693551 Phosphorylation of BRCA1-A complex at multiple sites by ATM R-HSA-5683385 Formation of BRCA1-A complex at DNA DSBs R-HSA-5683735 CHEK2 is recruited to DNA DSBs R-HSA-5683801 CHEK2 phosphorylates BRCA1 R-HSA-69891 Phosphorylation and activation of CHEK2 by ATM R-HSA-5684052 PIAS4 SUMOylates MDC1 R-HSA-5686685 RIF1 and PAX1IP bind TP53BP1 at DNA DSBs R-HSA-5686900 TP53BP1 recruits DCLRE1C to ATM R-HSA-5686704 Activated ATM phosphorylates DCLRE1C R-HSA-5693565 Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks R-HSA-5693607 Processing of DNA double-strand break ends R-HSA-5693571 Nonhomologous End-Joining (NHEJ) R-HSA-5693606 DNA Double Strand Break Response R-HSA-5693567 HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA) R-HSA-5693532 DNA Double-Strand Break Repair R-HSA-5693538 Homology Directed Repair R-HSA-73894 DNA Repair R-HSA-69473 G2/M DNA damage checkpoint R-HSA-69481 G2/M Checkpoints R-HSA-69620 Cell Cycle Checkpoints R-HSA-1640170 Cell Cycle
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
