The carboxyl-terminal of BRCA1 is required for subnuclear assembly of RAD51 after treatment with cisplatin but not ionizing radiation in human breast and ovarian cancer cells.
BRCA1 plays an important role in maintaining genomic stability through its involvement in DNA repair. Although it is known that BRCA1 and RAD51 form distinct DNA repair subnuclear complexes, or foci, following environmental insults to the DNA, the role of BRCA1 in this process remains to be characterized. The purpose of the study was therefore to determine the role of BRCA1 in the formation of RAD51 foci following treatment with cisplatin and ionizing radiation. We found that although a functional BRCA1 is required for the subnuclear assembly of BRCA1 foci following treatment with either ionizing radiation or cisplatin, a functional BRCA1 is required for RAD51 foci to form following treatment with cisplatin but not with ionizing radiation. Similar results were obtained in SKOV-3 cells when the level of BRCA1 expression was knocked down by stable expression of a retrovirus-mediated small-interfering RNA against BRCA1. We also found that the carboxyl-terminal of BRCA1 contains uncharacterized phosphorylation sites that are responsive to cisplatin. The functional BRCA1 is also required for breast and ovarian cancer cells to mount resistance to cisplatin. These results suggest that the carboxyl-terminal of BRCA1 is required for the cisplatin-induced recruitment of RAD51 to the DNA-damage site, which may contribute to cisplatin resistance.
Zhou
Chenyi
C
Department of Pathology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4095, USA.
Huang
Peng
P
Liu
Jinsong
J
D000970:Antineoplastic Agents / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000032:analysis / Q000737:chemistry / Q000502:physiology*; D001943:Breast Neoplasms / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D019398:Genes, BRCA1; D006801:Humans; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D034622:RNA Interference; D051135:Rad51 Recombinase; D011839:Radiation, Ionizing; D017384:Sequence Deletion
D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D004268:DNA-Binding Proteins; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D002945:Cisplatin