UniProt functional annotation for Q8IYW5



	UniProt functional annotation for Q8IYW5

UniProt code: Q8IYW5.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: E3 ubiquitin-protein ligase required for accumulation of repair proteins to sites of DNA damage. Acts with UBE2N/UBC13 to amplify the 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 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 TP53BP1 and 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 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. 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 JMJD2A/KDM4A in collaboration with RNF8, leading to unmask H4K20me2 mark and promote the recruitment of TP53BP1 at DNA damage sites. Not able to initiate 'Lys-63'-linked ubiquitination in vitro; possibly due to partial occlusion of the UBE2N/UBC13-binding region. Catalyzes monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub, respectively). {ECO:0000255|HAMAP-Rule:MF_03066, ECO:0000269|PubMed:19203578, ECO:0000269|PubMed:19203579, ECO:0000269|PubMed:20550933, ECO:0000269|PubMed:22373579, ECO:0000269|PubMed:22705371, ECO:0000269|PubMed:22713238, ECO:0000269|PubMed:22742833, ECO:0000269|PubMed:22980979, ECO:0000269|PubMed:23760478}.

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; Evidence={ECO:0000255|HAMAP-Rule:MF_03066};

Pathway: Protein modification; protein ubiquitination. {ECO:0000255|HAMAP-Rule:MF_03066}.

Subunit: Monomer. Interacts with UBE2N/UBC13. {ECO:0000255|HAMAP- Rule:MF_03066, ECO:0000269|PubMed:19203578, ECO:0000269|PubMed:22589545}.

Subcellular location: Nucleus {ECO:0000255|HAMAP-Rule:MF_03066, ECO:0000269|PubMed:19203578, ECO:0000269|PubMed:19203579, ECO:0000269|PubMed:19500350, ECO:0000269|PubMed:21041483, ECO:0000269|PubMed:22742833}. Note=Localizes to double-strand breaks (DSBs) sites of DNA damage. {ECO:0000255|HAMAP-Rule:MF_03066}.

Domain: The MIU motif (motif interacting with ubiquitin) mediates the interaction with both 'Lys-48'- and 'Lys-63'-linked ubiquitin chains (PubMed:19500350). The UMI motif mediates interaction with ubiquitin with a preference for 'Lys-63'-linked ubiquitin (PubMed:21041483). The specificity for different types of ubiquitin is mediated by juxtaposition of ubiquitin-binding motifs (MIU and UMI motifs) with LR motifs (LRMs) (PubMed:22742833). {ECO:0000255|HAMAP-Rule:MF_03066, ECO:0000269|PubMed:19500350, ECO:0000269|PubMed:21041483, ECO:0000269|PubMed:22742833}.

Ptm: Sumoylated with SUMO1 by PIAS4 in response to double-strand breaks (DSBs). {ECO:0000255|HAMAP-Rule:MF_03066, ECO:0000269|PubMed:22508508}.

Ptm: Ubiquitinated. {ECO:0000255|HAMAP-Rule:MF_03066, ECO:0000269|PubMed:19500350, ECO:0000269|PubMed:21041483}.

Disease: Riddle syndrome (RIDL) [MIM:611943]: An autosomal recessive disorder characterized by increased radiosensitivity, immunodeficiency, mild motor control and learning difficulties, facial dysmorphism, and short stature. {ECO:0000269|PubMed:19203578}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the RNF168 family. {ECO:0000255|HAMAP- Rule:MF_03066}.

Sequence caution: Sequence=BAC04060.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		E3 ubiquitin-protein ligase required for accumulation of repair proteins to sites of DNA damage. Acts with UBE2N/UBC13 to amplify the 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 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 TP53BP1 and 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 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. 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 JMJD2A/KDM4A in collaboration with RNF8, leading to unmask H4K20me2 mark and promote the recruitment of TP53BP1 at DNA damage sites. Not able to initiate 'Lys-63'-linked ubiquitination in vitro; possibly due to partial occlusion of the UBE2N/UBC13-binding region. Catalyzes monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub, respectively). {ECO:0000255\|HAMAP-Rule:MF_03066, ECO:0000269\|PubMed:19203578, ECO:0000269\|PubMed:19203579, ECO:0000269\|PubMed:20550933, ECO:0000269\|PubMed:22373579, ECO:0000269\|PubMed:22705371, ECO:0000269\|PubMed:22713238, ECO:0000269\|PubMed:22742833, ECO:0000269\|PubMed:22980979, ECO:0000269\|PubMed:23760478}.


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; Evidence={ECO:0000255\|HAMAP-Rule:MF_03066};
Pathway:		Protein modification; protein ubiquitination. {ECO:0000255\|HAMAP-Rule:MF_03066}.
Subunit:		Monomer. Interacts with UBE2N/UBC13. {ECO:0000255\|HAMAP- Rule:MF_03066, ECO:0000269\|PubMed:19203578, ECO:0000269\|PubMed:22589545}.
Subcellular location:		Nucleus {ECO:0000255\|HAMAP-Rule:MF_03066, ECO:0000269\|PubMed:19203578, ECO:0000269\|PubMed:19203579, ECO:0000269\|PubMed:19500350, ECO:0000269\|PubMed:21041483, ECO:0000269\|PubMed:22742833}. Note=Localizes to double-strand breaks (DSBs) sites of DNA damage. {ECO:0000255\|HAMAP-Rule:MF_03066}.
Domain:		The MIU motif (motif interacting with ubiquitin) mediates the interaction with both 'Lys-48'- and 'Lys-63'-linked ubiquitin chains (PubMed:19500350). The UMI motif mediates interaction with ubiquitin with a preference for 'Lys-63'-linked ubiquitin (PubMed:21041483). The specificity for different types of ubiquitin is mediated by juxtaposition of ubiquitin-binding motifs (MIU and UMI motifs) with LR motifs (LRMs) (PubMed:22742833). {ECO:0000255\|HAMAP-Rule:MF_03066, ECO:0000269\|PubMed:19500350, ECO:0000269\|PubMed:21041483, ECO:0000269\|PubMed:22742833}.
Ptm:		Sumoylated with SUMO1 by PIAS4 in response to double-strand breaks (DSBs). {ECO:0000255\|HAMAP-Rule:MF_03066, ECO:0000269\|PubMed:22508508}.
Ptm:		Ubiquitinated. {ECO:0000255\|HAMAP-Rule:MF_03066, ECO:0000269\|PubMed:19500350, ECO:0000269\|PubMed:21041483}.
Disease:		Riddle syndrome (RIDL) [MIM:611943]: An autosomal recessive disorder characterized by increased radiosensitivity, immunodeficiency, mild motor control and learning difficulties, facial dysmorphism, and short stature. {ECO:0000269\|PubMed:19203578}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the RNF168 family. {ECO:0000255\|HAMAP- Rule:MF_03066}.
Sequence caution:		Sequence=BAC04060.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};