TGF beta 1/Smad3 counteracts BRCA1-dependent repair of DNA damage

• Published in: Oncogene Vol. 24; no. 14; pp. 2289 - 2297
• Main Authors: Dubrovska, A, Kanamoto, T, Lomnytska, M, Heldin, C-H, Volodko, N, Souchelnytskyi, S
• Format: Journal Article
• Language: English
• Published: 31.03.2005
• DOI: 10.1038/sj.onc.1208443
• ISSN: 0950-9232

Inactivation of the BRCA1 gene has been found to confer susceptibility to early-onset familial breast and ovarian cancers. BRCA1 regulates DNA repair, chromatin remodeling and affects gene transcription. Transforming growth factor- beta (TGF beta ) is a potent regulator of growth, apoptosis and invasiveness of tumor cells, including breast cancer cells. Here we show that Smad3 which is a component of the TGF beta signaling pathway, forms a complex with BRCA1 in vitro and in vivo. The interaction is mediated by the MH1 domain of Smad3 and the C-terminal part of BRCA1. We observed a co-localization of Smad3 and BRCA1 in nuclear complexes. We also found that TGF beta 1/Smad3 counteracted BRCA1-dependent repair of DNA double-strand breaks in human breast epithelial cells, as evaluated by BRCA1 nuclear foci formation, single-cell gel electrophoresis and cell survival assays. Thus, TGF beta 1/Smad3 suppresses BRCA1-dependent DNA repair in response to a DNA damaging agent.