Format

Send to

Choose Destination
Mol Cell. 2015 Jul 16;59(2):176-87. doi: 10.1016/j.molcel.2015.05.032. Epub 2015 Jul 2.

Promotion of BRCA2-Dependent Homologous Recombination by DSS1 via RPA Targeting and DNA Mimicry.

Author information

1
Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
2
Departments of Biochemistry and Chemistry, and Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA.
3
Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA.
4
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
5
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
6
Departments of Biochemistry and Chemistry, and Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: walter.chazin@vanderbilt.edu.
7
Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA; Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
8
Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: patrick.sung@yale.edu.

Abstract

The tumor suppressor BRCA2 is thought to facilitate the handoff of ssDNA from replication protein A (RPA) to the RAD51 recombinase during DNA break and replication fork repair by homologous recombination. However, we find that RPA-RAD51 exchange requires the BRCA2 partner DSS1. Biochemical, structural, and in vivo analyses reveal that DSS1 allows the BRCA2-DSS1 complex to physically and functionally interact with RPA. Mechanistically, DSS1 acts as a DNA mimic to attenuate the affinity of RPA for ssDNA. A mutation in the solvent-exposed acidic domain of DSS1 compromises the efficacy of RPA-RAD51 exchange. Thus, by targeting RPA and mimicking DNA, DSS1 functions with BRCA2 in a two-component homologous recombination mediator complex in genome maintenance and tumor suppression. Our findings may provide a paradigm for understanding the roles of DSS1 in other biological processes.

PMID:
26145171
PMCID:
PMC4506714
DOI:
10.1016/j.molcel.2015.05.032
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center