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RNF4-dependent hybrid SUMO-ubiquitin chains are signals for RAP80 and thereby mediate the recruitment of BRCA1 to sites of DNA damage.

Science signaling | Dec 4, 2012

The DNA repair function of the breast cancer susceptibility protein BRCA1 depends in part on its interaction with RAP80, which targets BRCA1 to DNA double-strand breaks (DSBs) through recognition of K63-linked polyubiquitin chains. The localization of BRCA1 to DSBs also requires sumoylation. We demonstrated that, in addition to having ubiquitin-interacting motifs, RAP80 also contains a SUMO-interacting motif (SIM) that is critical for recruitment to DSBs. In combination with the ubiquitin-binding activity of RAP80, this SIM enabled RAP80 to bind with nanomolar affinity to hybrid chains consisting of ubiquitin conjugated to SUMO. Furthermore, RNF4, a SUMO-targeted ubiquitin E3 ligase that synthesizes hybrid SUMO-ubiquitin chains, localized to DSBs and was critical for the recruitment of RAP80 and BRCA1 to sites of DNA damage. Our findings, therefore, connect ubiquitin- and SUMO-dependent DSB recognition, revealing that RNF4-synthesized hybrid SUMO-ubiquitin chains are recognized by RAP80 to promote BRCA1 recruitment and DNA repair.

Pubmed ID: 23211528 RIS Download

Mesh terms: Amino Acid Motifs | BRCA1 Protein | Carrier Proteins | Cell Line, Tumor | DNA Breaks, Double-Stranded | DNA Repair | Humans | Nuclear Proteins | SUMO-1 Protein | Sumoylation | Transcription Factors | Ubiquitin-Protein Ligases | Ubiquitins

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Associated grants

  • Agency: NIGMS NIH HHS, Id: R01 GM060980
  • Agency: NIGMS NIH HHS, Id: U54 GM103520

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