American Association for Cancer Research
Browse
00085472can103119-sup-sfig_6.pdf (621.17 kB)

Supplementary Figure 6 from Bcl-2 Inhibits Nuclear Homologous Recombination by Localizing BRCA1 to the Endomembranes

Download (621.17 kB)
journal contribution
posted on 2023-03-30, 20:27 authored by Corentin Laulier, Aurélia Barascu, Josée Guirouilh-Barbat, Gaëlle Pennarun, Catherine Le Chalony, François Chevalier, Gaëlle Palierne, Pascale Bertrand, Jean Marc Verbavatz, Bernard S. Lopez
Supplementary Figure 6 from Bcl-2 Inhibits Nuclear Homologous Recombination by Localizing BRCA1 to the Endomembranes

History

ARTICLE ABSTRACT

Genetic stability requires coordination of a network of pathways including DNA repair/recombination and apoptosis. In addition to its canonical anti-apoptotic role, Bcl-2 negatively impacts genome stability. In this study, we identified the breast cancer tumor suppressor BRCA1, which plays an essential role in homologous recombination (HR), as a target for Bcl-2 in the repression of HR. Indeed, ionizing radiation–induced BRCA1 foci assembly was repressed when Bcl-2 was expressed ectopically, in human SV40 fibroblasts, or spontaneously, in lymphoma t(14:18) cells and in HeLa and H460 cancer cell lines. Moreover, we showed that the transmembrane (TM) domain of Bcl-2 was required for both inhibition of BRCA1 foci assembly and the inhibition of HR induced by a double-strand break targeted into an intrachromosomal HR substrate by the meganuclease I-SceI. Fluorescence confocal microscopy, proximity ligation assay, and electron microscopy analyses as well as Western blot analysis of subcellular fractions showed that Bcl-2 and BRCA1 colocalized to mitochondria and endoplasmic reticulum in a process requiring the TM domain of Bcl-2. Targeting BRCA1 to the endomembranes depletes BRCA1 from the nucleus and, thus, accounts for the inhibition of HR. Furthermore, our findings support an apoptosis-stimulatory role for the cytosolic form of BRCA1, suggesting a new tumor suppressor function of BRCA1. Together, our results reveal a new mode of BRCA1 regulation and for HR in the maintenance of genome stability. Cancer Res; 71(10); 3590–602. ©2011 AACR.