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Sci. Signal., 4 December 2012
Vol. 5, Issue 253, p. ra88
[DOI: 10.1126/scisignal.2003485]

RESEARCH ARTICLES

RNF4-Dependent Hybrid SUMO-Ubiquitin Chains Are Signals for RAP80 and Thereby Mediate the Recruitment of BRCA1 to Sites of DNA Damage

Catherine M. Guzzo1, Christopher E. Berndsen2*, Jianmei Zhu1, Vibhor Gupta3, Ajit Datta2{dagger}, Roger A. Greenberg3, Cynthia Wolberger2, and Michael J. Matunis1{ddagger}

1 Department of Biochemistry and Molecular Biology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA.
2 Department of Biophysics and Biophysical Chemistry and the Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
3 Department of Cancer Biology and Department of Pathology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

* Present address: Department of Chemistry and Biochemistry, James Madison University, Harrisonburg, VA 22807, USA.

{dagger} Present address: Department of Biochemistry, Bose Institute, P-1/12 CIT Scheme VIIM, Kolkata 700054, India.

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.

{ddagger} To whom correspondence should be addressed. E-mail: mmatunis{at}jhsph.edu

Citation: C. M. Guzzo, C. E. Berndsen, J. Zhu, V. Gupta, A. Datta, R. A. Greenberg, C. Wolberger, M. J. Matunis, RNF4-Dependent Hybrid SUMO-Ubiquitin Chains Are Signals for RAP80 and Thereby Mediate the Recruitment of BRCA1 to Sites of DNA Damage. Sci. Signal. 5, ra88 (2012).

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