Abstract |
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.
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Authors | Catherine M Guzzo, Christopher E Berndsen, Jianmei Zhu, Vibhor Gupta, Ajit Datta, Roger A Greenberg, Cynthia Wolberger, Michael J Matunis |
Journal | Science signaling
(Sci Signal)
Vol. 5
Issue 253
Pg. ra88
(Dec 04 2012)
ISSN: 1937-9145 [Electronic] United States |
PMID | 23211528
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- BRCA1 Protein
- BRCA1 protein, human
- Carrier Proteins
- DNA-Binding Proteins
- Histone Chaperones
- Nuclear Proteins
- RNF4 protein, human
- SUMO-1 Protein
- Transcription Factors
- UIMC1 protein, human
- Ubiquitins
- Ubiquitin-Protein Ligases
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Topics |
- Amino Acid Motifs
- BRCA1 Protein
(genetics, metabolism)
- Carrier Proteins
(genetics, metabolism)
- Cell Line, Tumor
- DNA Breaks, Double-Stranded
- DNA Repair
(physiology)
- DNA-Binding Proteins
- Histone Chaperones
- Humans
- Nuclear Proteins
(genetics, metabolism)
- SUMO-1 Protein
(genetics, metabolism)
- Sumoylation
- Transcription Factors
(genetics, metabolism)
- Ubiquitin-Protein Ligases
(genetics, metabolism)
- Ubiquitins
(genetics, metabolism)
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