TGF beta 1/Smad3 counteracts BRCA1-dependent repair of DNA damage
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 inva...
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Published in | Oncogene Vol. 24; no. 14; pp. 2289 - 2297 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
31.03.2005
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Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 content type line 23 ObjectType-Feature-1 |
ISSN: | 0950-9232 |
DOI: | 10.1038/sj.onc.1208443 |