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Annotation rule MF_03067
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General rule information [?]

Accession MF_03067
Dates 5-MAR-2009 (Created)
20-NOV-2019 (Last updated, Version 6)
Name RNF8
Scope
Eukaryota; Vertebrata
Templates O76064 (RNF8_HUMAN); Q8VC56 (RNF8_MOUSE): [Recover all]

Propagated annotation [?]


Identifier, protein and gene names [?]

Identifier
RNF8
case <OC:Mammalia>
Protein name
RecName: Full=E3 ubiquitin-protein ligase RNF8;
EC 2.3.2.27;
AltName: Full=RING finger protein 8;
AltName: Full=RING-type E3 ubiquitin transferase RNF8;
else
Protein name
RecName: Full=E3 ubiquitin-protein ligase ;
EC 2.3.2.27;
AltName: Full=RING finger protein 8;
AltName: Full=RING-type E3 ubiquitin transferase ;
end case
Gene name
RNF8

Comments [?]

case <OC:Mammalia>
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. 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. 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.
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 phosphorylated HERC2 (via C-terminus). Interacts with PIWIL1; leading to sequester RNF8 in the cytoplasm.
Subcellular location Nucleus. Cytoplasm. Midbody. Chromosome, telomere. Note=Recruited at uncapped telomeres. 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. During spermatogenesis, sequestered in the cytoplasm by PIWIL1: RNF8 is released following ubiquitination and degradation of PIWIL1.
Domain The FHA domain specifically recognizes and binds ATM-phosphorylated MDC1 and phosphorylated HERC2.
else
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 @gn(MDC1) and catalyzes the 'Lys-63'-linked ubiquitination of histones H2A and H2AX, thereby promoting the formation of @gn(TP53BP1) and @gn(BRCA1) ionizing radiation-induced foci (IRIF). 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. Also catalyzes the formation of 'Lys-48'-linked polyubiquitin chains, leading to degradation of substrate proteins. In addition to its function in damage signaling, also plays a role in higher-order chromatin structure by mediating extensive chromatin decondensation.
Subunit Homodimer. Forms a E2-E3 ubiquitin ligase complex composed of the @gn(RNF8) homodimer and a E2 heterodimer of @gn(UBE2N) and @gn(UBE2V2).
Subcellular location Nucleus. Note=Following DNA double-strand breaks, recruited to the sites of damage.
Domain The FHA domain specifically recognizes and binds ATM-phosphorylated MDC1.
end case
Catalytic activity Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.; EC=2.3.2.27;
Pathway Protein modification; protein ubiquitination.
case <OC:Mammalia>
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.
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. 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). 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. Additional evidences are however required to confirm these data.
end case
Similarity Belongs to the RNF8 family.

Keywords [?]

case <OC:Mammalia>
end case

Gene Ontology [?]

GO:0003682; Molecular function: chromatin binding.
GO:0042393; Molecular function: histone binding.
GO:0043130; Molecular function: ubiquitin binding.
GO:0004842; Molecular function: ubiquitin-protein transferase activity.
GO:0045739; Biological process: positive regulation of DNA repair.
GO:0010212; Biological process: response to ionizing radiation.
GO:0006302; Biological process: double-strand break repair.
GO:0033522; Biological process: histone H2A ubiquitination.
GO:0033523; Biological process: histone H2B ubiquitination.
GO:0000151; Cellular component: ubiquitin ligase complex.
GO:0005634; Cellular component: nucleus.

Cross-references [?]

PROSITE PS50006; FHA_DOMAIN; 1; trigger=PRU00086;
PS00518; ZF_RING_1; 1;
PS50089; ZF_RING_2; 1; trigger=PRU00175;
PS50322; GLN_RICH; 0-unlimited;
Pfam PF00498; FHA; 1;

Features [?]

case <OC:Mammalia>
From: RNF8_MOUSE (Q8VC56)
Key     From     To       Description   Tag   Condition   FTGroup
REGION     68     72       Required for interaction with PIWIL1        
end case

Additional information [?]

Size range 457-550 amino acids
Related rules None
Fusion None