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HAMAP rule MF_03066

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General rule information [?]

Accession MF_03066
Dates 5-MAR-2009 (Created)
20-NOV-2019 (Last updated, Version 5)
Name RNF168
Scope
Eukaryota; Vertebrata
Template Q8IYW5 (RN168_HUMAN)
Triggered by

Propagated annotation [?]


Identifier, protein and gene names [?]

Identifier
RN168
case <OC:Mammalia>
Protein name
RecName: Full=E3 ubiquitin-protein ligase RNF168;
EC 2.3.2.27;
AltName: Full=RING finger protein 168;
AltName: Full=RING-type E3 ubiquitin transferase RNF168;
else
Protein name
RecName: Full=E3 ubiquitin-protein ligase ;
EC 2.3.2.27;
AltName: Full=RING finger protein 168;
AltName: Full=RING-type E3 ubiquitin transferase ;
end case
Gene name
RNF168

Comments [?]

case <OC:Mammalia>
Function E3 ubiquitin-protein ligase required for accumulation of repair proteins to sites of DNA damage. Acts with @gn(UBE2N)/@gn(UBC13) to amplify the @gn(RNF8)-dependent histone ubiquitination. Recruited to sites of DNA damage at double-strand breaks (DSBs) by binding to ubiquitinated histone H2A and H2AX and amplifies the @gn(RNF8)-dependent H2A ubiquitination, promoting the formation of 'Lys-63'-linked ubiquitin conjugates. This leads to concentrate ubiquitinated histones H2A and H2AX at DNA lesions to the threshold required for recruitment of @gn(TP53BP1) and @gn(BRCA1). Also recruited at DNA interstrand cross-links (ICLs) sites and promotes accumulation of 'Lys-63'-linked ubiquitination of histones H2A and H2AX, leading to recruitment of @gn(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. Also involved in class switch recombination in immune system, via its role in regulation of DSBs repair. Following DNA damage, promotes the ubiquitination and degradation of @gn(JMJD2A)/@gn(KDM4A) in collaboration with @gn(RNF8), leading to unmask H4K20me2 mark and promote the recruitment of @gn(TP53BP1) at DNA damage sites. Not able to initiate 'Lys-63'-linked ubiquitination in vitro; possibly due to partial occlusion of the @gn(UBE2N)/@gn(UBC13)-binding region. Catalyzes monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub, respectively).
Subunit Monomer. Interacts with UBE2N/UBC13.
else
Function E3 ubiquitin-protein ligase required for accumulation of repair proteins to sites of DNA damage. Acts with @gn(UBE2N)/@gn(UBC13) to amplify the @gn(RNF8)-dependent histone ubiquitination. Recruited to sites of DNA damage at double-strand breaks (DSBs) by binding to ubiquitinated histone H2A and ubiquitinates histone H2A and H2AX, leading to amplify the @gn(RNF8)-dependent H2A ubiquitination and promoting the formation of 'Lys-63'-linked ubiquitin conjugates. This leads to concentrate ubiquitinated histones H2A and H2AX at DNA lesions to the threshold required for recruitment of @gn(TP53BP1) and @gn(BRCA1). Catalyzes monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub, respectively).
Subunit Monomer.
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.
Subcellular location Nucleus. Note=Localizes to double-strand breaks (DSBs) sites of DNA damage.
Domain The MIU motif (motif interacting with ubiquitin) mediates the interaction with both 'Lys-48'- and 'Lys-63'-linked ubiquitin chains. The UMI motif mediates interaction with ubiquitin with a preference for 'Lys-63'-linked ubiquitin. The specificity for different types of ubiquitin is mediated by juxtaposition of ubiquitin-binding motifs (MIU and UMI motifs) with LR motifs (LRMs).
case <OC:Mammalia>
Ptm Sumoylated with @gn(SUMO1) by @gn(PIAS4) in response to double-strand breaks (DSBs).
Ubiquitinated.
Caution According to a well-established model, @gn(RNF168) cannot initiate H2A 'Lys-63'-linked ubiquitination and is recruited following @gn(RNF8)-dependent histone ubiquitination to amplify H2A 'Lys-63'-linked ubiquitination. However, other data suggest that @gn(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 @gn(RNF168) might be recruited to DSBs sites in a @gn(RNF8)-dependent manner by binding to non-histone proteins ubiquitinated via 'Lys-63'-linked and initiates monoubiquitination of H2A, which is then amplified by @gn(RNF8). Additional evidences are however required to confirm these data.
end case
Similarity Belongs to the RNF168 family.

Keywords [?]

Chromatin regulator
DNA damage
DNA repair
Metal-binding
Nucleus
Transferase
case <OC:Mammalia>
Ubl conjugation
end case
Ubl conjugation pathway
Zinc
Zinc-finger

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:0000151; Cellular component: ubiquitin ligase complex.
GO:0005634; Cellular component: nucleus.

Cross-references [?]

PROSITE PS00518; ZF_RING_1; 1;
PS50089; ZF_RING_2; 1; trigger=PRU00175;
PS50313; GLU_RICH; 0-unlimited;

Features [?]

From: RN168_HUMAN (Q8IYW5)
Key     From     To       Description   Tag   Condition   FTGroup
MOTIF     110     128       LR motif 1     [ILV]-[SC]-[KQE]-P-G-E-[ILV]-R-[RQK]-E-Y-E-x-[EQ]-[ILV]-x-[RK]-x(2)  
MOTIF     143     151       UMI motif     E-[EDQ]-Y-I-[RQ]-[RK]-L-L-A  
MOTIF     168     191       MIU motif 1     x-E-[EKQR]-Q-[LM]-[KRLE]-x-D-E-x-L-A-[RW]-x-[LIV]-S-x-[DSNKEQ]-[LMI]-[DN]-x(1,4)  
MOTIF     439     462       MIU motif 2     R-[RHYWQ]-[RKQ]-Q-E-[EK]-[QHED]-D-[RH]-x-[LF]-A-L-[QER]-[LI]-Q-[RKE]-[EQ]-x-[DNEK]-[KQR]-[ER]-x(2)  
MOTIF     466     477       LR motif 2     R-x-[KN]-G-S-x(3)-Y-x-L-R  

Additional information [?]

Size range 422-577 amino acids
Related rules None
Fusion None


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