Tbio RNF8 E3 ubiquitin-protein ligase RNF8

Protein Summary

Description

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 (PubMed:11322894, PubMed:14981089, PubMed:17724460, PubMed:18001824, PubMed:18001825, PubMed:18006705, PubMed:18077395, PubMed:18337245, PubMed:18948756, PubMed:19015238, PubMed:19124460, PubMed:19202061, PubMed:19203578, PubMed:19203579, PubMed:20550933, PubMed:21558560, PubMed:21857671, PubMed:21911360, PubMed:22266820, PubMed:22373579, PubMed:22531782, PubMed:22705371, PubMed:22865450, PubMed:22980979). Following DNA damage, mediates the ubiquitination and degradation of POLD4/p12, a subunit of DNA polymerase delta. In the absence of POLD4, DNA polymerase delta complex exhibits higher proofreading activity (PubMed:23233665). 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 (PubMed:11322894, PubMed:14981089, PubMed:17724460, PubMed:18001824, PubMed:18001825, PubMed:18006705, PubMed:18077395, PubMed:18337245, PubMed:18948756, PubMed:19015238, PubMed:19124460, PubMed:19202061, PubMed:19203578, PubMed:19203579, PubMed:20550933, PubMed:21558560, PubMed:21857671, PubMed:21911360, PubMed:22266820, PubMed:22373579, PubMed:22531782, PubMed:22705371, PubMed:22865450, PubMed:22980979). The protein encoded by this gene contains a RING finger motif and an FHA domain. This protein has been shown to interact with several class II ubiquitin-conjugating enzymes (E2), including UBE2E1/UBCH6, UBE2E2, and UBE2E3, and may act as an ubiquitin ligase (E3) in the ubiquitination of certain nuclear proteins. This protein is also known to play a role in the DNA damage response and depletion of this protein causes cell growth inhibition and cell cycle arrest. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

Uniprot Accession IDs

• O76064
• A6NN24
• A8MYC0
• B4DPG0
• Q53H16
• Q5NKW5
• hRNF8

Gene Name

• RNF8

Ensembl ID

• ENST00000229866
• ENSP00000229866
• ENSG00000112130
• ENST00000373479
• ENSP00000362578
• ENST00000469731
• ENSP00000418879

Symbol

• KIAA0646
• hRNF8

Knowledge Table

Most Knowledge About	Knowledge Value (0 to 1 scale)
disease perturbation	0.96
biological process	0.95
virus perturbation	0.92
protein domain	0.85
microRNA	0.82

Protein Classes

No PANTHER Classes or DTO Classes found

IDG Development Level Summary

Tdark

These are targets about which virtually nothing is known. They do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 107.17   (req: < 5)

Gene RIFs: 76   (req: <= 3)

Antibodies: 309   (req: <= 50)

Tbio

These targets do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 107.17   (req: >= 5)

Gene RIFs: 76   (req: > 3)

Antibodies: 309   (req: > 50)

- OR - satisfy the following criterion:

Gene Ontology Terms: 28

Tchem

Target has at least one ChEMBL compound with an activity cutoff of < 30 nM - AND - satisfies the preceding conditions

Active Ligand: 0

Tclin

Target has at least one approved drug - AND - satisfies the preceding conditions

Active Drug: 0