Mus musculus Protein: Rnf8
InnateDB Protein IDBP-160895.6
Last Modified 2014-10-13 [Report errors or provide feedback]
Gene Symbol Rnf8
Protein Name ring finger protein 8
Synonyms 3830404E21Rik; AIP37;
Species Mus musculus
Ensembl Protein ENSMUSP00000024817
InnateDB Gene IDBG-486177 (Rnf8)
Protein Structure
UniProt Annotation
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 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 aggravating 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. {ECO:0000269PubMed:20080757, ECO:0000269PubMed:20153262, ECO:0000269PubMed:21706008, ECO:0000269PubMed:21857671, ECO:0000269PubMed:22266820}.
Subcellular Localization Nucleus {ECO:0000250}. Midbody {ECO:0000250}. Chromosome, telomere {ECO:0000269PubMed:21857671, ECO:0000269PubMed:22101936}. Note=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 (By similarity). Recruited at uncapped telomeres. {ECO:0000250}.
Disease Associations
Tissue Specificity
Number of Interactions This gene and/or its encoded proteins are associated with 3 experimentally validated interaction(s) in this database.
Experimentally validated
Total 3 [view]
Protein-Protein 3 [view]
Protein-DNA 0
Protein-RNA 0
Gene Ontology

Molecular Function
Accession GO Term
GO:0003682 chromatin binding
GO:0004842 ubiquitin-protein transferase activity
GO:0005515 protein binding
GO:0008270 zinc ion binding
GO:0016881 acid-amino acid ligase activity
GO:0042393 histone binding
GO:0042803 protein homodimerization activity
GO:0046872 metal ion binding
Biological Process
GO:0006302 double-strand break repair
GO:0006303 double-strand break repair via nonhomologous end joining
GO:0006511 ubiquitin-dependent protein catabolic process
GO:0006974 cellular response to DNA damage stimulus
GO:0007067 mitotic nuclear division
GO:0007286 spermatid development
GO:0010212 response to ionizing radiation
GO:0016567 protein ubiquitination
GO:0033522 histone H2A ubiquitination
GO:0033523 histone H2B ubiquitination
GO:0043486 histone exchange
GO:0045190 isotype switching
GO:0045739 positive regulation of DNA repair
GO:0045900 negative regulation of translational elongation
GO:0051301 cell division
GO:0070534 protein K63-linked ubiquitination
GO:0070535 histone H2A K63-linked ubiquitination
GO:0070936 protein K48-linked ubiquitination
Cellular Component
GO:0000151 ubiquitin ligase complex
GO:0000781 chromosome, telomeric region
GO:0005634 nucleus
GO:0030496 midbody
GO:0035861 site of double-strand break
Protein Structure and Domains
PDB ID MGI:1929069
InterPro IPR000253 Forkhead-associated (FHA) domain
IPR001841 Zinc finger, RING-type
IPR008984 SMAD/FHA domain
IPR017335 E3 ubiquitin ligase, RNF8
IPR018957 Zinc finger, C3HC4 RING-type
PFAM PF00498
Post-translational Modifications
SwissProt Q8VC56
PhosphoSite PhosphoSite-Q8VC56
UniProt Splice Variant
Entrez Gene 58230
UniGene Mm.305994
RefSeq NP_067394
MGI Symbol Rnf8
EMBL AC154279 AC163629 AJ242721 AK076180 AK147168 BC021778 CT010295
GenPept AAH21778 BAC36236 BAE27732 CAB92239 CAJ18503