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BRCA2 Function in DNA Binding and Recombination from a BRCA2-DSS1-ssDNA Structure
Haijuan Yang,1Philip D. Jeffrey,2Julie Miller,23Elspeth Kinnucan,2Yutong Sun,1Nicolas H. Thomä,2Ning Zheng,23Phang-Lang Chen,4Wen-Hwa Lee,4Nikola P. Pavletich23*
Mutations in the BRCA2 (breast cancer
susceptibility gene 2) tumor suppressor lead to chromosomal instability
due to defectsin the repair of double-strand DNA breaks (DSBs) by
homologousrecombination, but BRCA2's role in this process has been
unclear.Here, we present the 3.1 angstrom crystal structure of a
~90-kilodaltonBRCA2 domain bound to DSS1, which reveals three
oligonucleotide-binding(OB) folds and a helix-turn-helix (HTH) motif.
We also (i) demonstratethat this BRCA2 domain binds single-stranded
DNA, (ii) presentits 3.5 angstrom structure bound to
oligo(dT)9, (iii) providedata that implicate the
HTH motif in dsDNA binding, and (iv) showthat BRCA2 stimulates
RAD51-mediated recombination in vitro. Thesefindings establish that
BRCA2 functions directly in homologousrecombination and provide a
structural and biochemical basis forunderstanding the loss of
recombination-mediated DSB repair inBRCA2-associated cancers.
1 Department of Pharmacology, Sloan-Kettering
Division, Joan and Sanford I. Weill Graduate School of Medical
Sciences, Cornell University, New York, NY 10021, USA.
2 Cellular Biochemistry and Biophysics Program and
3 Howard Hughes Medical Institute, Memorial
Sloan-Kettering Cancer Center, New York, NY 10021, USA.
4 Department of Molecular Medicine and Institute of
Biotechnology, University of Texas Health Center, San Antonio, TX
78245, USA.
*
To whom correspondence should be addressed. E-mail:
nikola{at}xray2.mskcc.org
The editors suggest the following Related Resources on Science sites:
In Science Magazine
PERSPECTIVES
John H. Wilson and Stephen J. Elledge (13 September 2002) Science297 (5588), 1822.
[DOI: 10.1126/science.1077171] |Summary »|Full Text »|PDF »
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