InnateDB: Systems Biology of the Innate Immune Response

Mus musculus Protein: Rnf8

Summary

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

Comments

Interactions

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
DNA-DNA	0
RNA-RNA	0
DNA-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
PF13639
PF14634
PF00097

PRINTS

PIRSF

PIRSF037950

SMART

SM00240
SM00184

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt