an E3 ubiquitin-protein ligase that plays a key role in DNA damage signaling via 2 distinct roles: by mediating the ubiquitinylation 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). 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. Controls the recruitment of UIMC1-BRCC3 (RAP80-BRCC36) and PAXIP1/PTIP to DNA damage sites. Is recruited to DNA interstrand cross-link (ICLs) sites and catalyzes the 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 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. 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. 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. Ubiquitous. High expression in brain, thymus and liver in fetal tissues. In adult tissues, highest levels in brain and testis, lowest levels in peripheral blood cells. Belongs to the RNF8 family. Three alternatively spliced human isoforms have been reported. Note: This description may include information from UniProtKB.
Cellular Component: chromosome, telomeric region; cytosol; midbody; nucleoplasm; nucleus; site of double-strand break; ubiquitin ligase complex
Molecular Function: chromatin binding; histone binding; identical protein binding; protein binding; protein homodimerization activity; ubiquitin binding; ubiquitin protein ligase activity; ubiquitin protein ligase binding; ubiquitin-protein transferase activity; zinc ion binding
Biological Process: cell cycle; cell division; cellular response to DNA damage stimulus; double-strand break repair; double-strand break repair via nonhomologous end joining; histone H2A K63-linked ubiquitination; histone H2A ubiquitination; histone H2B ubiquitination; interstrand cross-link repair; isotype switching; negative regulation of transcription elongation by RNA polymerase II; positive regulation of DNA repair; protein autoubiquitination; protein K48-linked ubiquitination; protein K63-linked ubiquitination; protein ubiquitination; response to ionizing radiation; sperm DNA condensation; spermatid development; ubiquitin-dependent protein catabolic process
Alt. Names/Synonyms: C3HC4-type zinc finger protein; E3 ubiquitin-protein ligase RNF8; FLJ12013; hRNF8; KIAA0646; ring finger protein (C3HC4 type) 8; RING finger protein 8; ring finger protein 8, E3 ubiquitin protein ligase; RING-type E3 ubiquitin transferase RNF8; RNF8; UBC13/UEV-interacting ring finger protein