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Caspase-dependent BRCA1 cleavage facilitates chemotherapy-induced apoptosis

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Abstract

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.

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Acknowledgments

We thank I. Durand and Julie Pourchet for expert technical assistance, T. de France and L. Genestier for technical advice, P. Arrigo for scientific advice and discussion, and T. Renno and M.-D. Reynaud for critical reading of the manuscript. Financial support: Eva Dizin is a recipient of a fellowship from the French Ministry of Research. Hind Ray is a recipient of a fellowship from the Association pour la Recherche sur le Cancer. Florent Suau is a recipient of a fellowship from the Ligue Nationale Contre le Cancer. The present work was supported by the Ligue Nationale Contre le Cancer, Comité Départemental du Rhône and the Association pour la Recherche sur le Cancer.

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Author notes

  1. Eva Dizin

    Present address: Laboratory of Molecular Gynecology and Obstetrics, Department of Gynecology and Obstetrics, Geneva University Hospitals, Maternité, 30, Bld de la Cluse, 1211, Geneva, Switzerland

Authors and Affiliations

  1. Génétique Moléculaire Signalisation et Cancer, Université de Lyon, Lyon, 69373, France

    Eva Dizin, Hind Ray, Florent Suau & Nicole Dalla Venezia

  2. Laboratoire de Génétique Moléculaire Signalisation et Cancer, Faculté de Médecine Rockefeller, CNRS UMR 5201, 8 Avenue Rockefeller, Lyon Cedex 08, 69373, France

    Eva Dizin, Hind Ray, Florent Suau & Nicole Dalla Venezia

  3. Oncogenèse et Progression Tumorale, Université Lyon1, Centre Léon Bérard, INSERM U590, Lyon, France

    Thibault Voeltzel

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  1. Eva Dizin
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Correspondence to Nicole Dalla Venezia.

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Dizin, E., Ray, H., Suau, F. et al. Caspase-dependent BRCA1 cleavage facilitates chemotherapy-induced apoptosis. Apoptosis 13, 237–246 (2008). https://doi.org/10.1007/s10495-007-0167-4

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  • DOI: https://doi.org/10.1007/s10495-007-0167-4

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