Caspase-dependent BRCA1 cleavage facilitates chemotherapy-induced apoptosis.
BRCA1 acts as a tumor suppressor gene, and germ-line mutations in this gene are found in a large proportion of families with breast and ovarian cancers. The BRCA1 protein has been implicated in several cellular processes, such as transcription regulation, DNA responses to DNA damage signals, cell cycle control, and apoptosis. Apoptosis plays a critical role in radiation- and chemotherapy-induced cytotoxicity, and its impairment contributes to resistance to tumor treatments. In an attempt to elucidate the role of BRCA1 in apoptosis, we examined the response to chemotherapeutic drugs of cells expressing physiological levels of BRCA1 protein. We showed that chemotherapy-induced apoptosis leads to a caspase-mediated cleavage of BRCA1. We then showed that the BRCA1-p90 cleavage product is mainly localized in the cytoplasm. Finally, we demonstrated that cancer-associated mutations affecting the BRCT tandem repeat abolish its pro-apoptotic function. The data presented here provide new insight into the role of endogenous BRCA1 as a mediator of apoptosis and show that BRCA1 functions as a molecular determinant of response to a range of cytotoxic chemotherapeutic agents.
Dizin
Eva
E
Génétique Moléculaire Signalisation et Cancer, Université de Lyon, Lyon 69373, France.
Ray
Hind
H
Suau
Florent
F
Voeltzel
Thibault
T
Dalla Venezia
Nicole
N
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D019313:BRCA1 Protein / Q000378:metabolism*; D001943:Breast Neoplasms; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells
D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D020169:Caspases