Poly(ADP-Ribose) Mediates the BRCA2-Dependent Early DNA Damage Response.
Breast cancer susceptibility gene 2 (BRCA2) plays a key role in DNA damage repair for maintaining genomic stability. Previous studies have shown that BRCA2 contains three tandem oligonucleotide/oligosaccharide binding folds (OB-folds) that are involved in DNA binding during DNA double-strand break repair. However, the molecular mechanism of BRCA2 in DNA damage repair remains elusive. Unexpectedly, we found that the OB-folds of BRCA2 recognize poly(ADP-ribose) (PAR) and mediate the fast recruitment of BRCA2 to DNA lesions, which is suppressed by PARP inhibitor treatment. Cancer-associated mutations in the OB-folds of BRCA2 disrupt the interaction with PAR and abolish the fast relocation of BRCA2 to DNA lesions. The quickly recruited BRCA2 is important for the early recruitment of exonuclease 1(EXO1) and is involved in DNA end resection, the first step of homologous recombination (HR). Thus, these findings uncover a molecular mechanism by which BRCA2 participates in DNA damage repair.
College of Life and Environment Sciences, Shanghai Normal University, Guilin Road 100, Shanghai 200234, China; Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, 1150 W. Medical Center Drive, 5560 MSRBII, Ann Arbor, MI 48109, USA.
Feng
F
Zhang
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, 1150 W. Medical Center Drive, 5560 MSRBII, Ann Arbor, MI 48109, USA; Department of Cell Biology, the Third Military Medical University, Chongqing 400038, China.
Jiazhong
J
Shi
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, 1150 W. Medical Center Drive, 5560 MSRBII, Ann Arbor, MI 48109, USA; Department of Radiation Biology, Beckman Research Institute, City of Hope, Duarte, CA 91773, USA.
Chunjing
C
Bian
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, 1150 W. Medical Center Drive, 5560 MSRBII, Ann Arbor, MI 48109, USA; Department of Radiation Biology, Beckman Research Institute, City of Hope, Duarte, CA 91773, USA. Electronic address: xyu@coh.org.
Xiaochun
X
Yu
D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D008954:Models, Biological; D011064:Poly Adenosine Diphosphate Ribose / Q000235:genetics / Q000378:metabolism*
D024682:BRCA2 Protein; D011064:Poly Adenosine Diphosphate Ribose