TGFbeta1/Smad3 counteracts BRCA1-dependent repair of DNA damage
2005 (English)In: Oncogene, ISSN 0950-9232, Vol. 24, no 14, 2289-2297 p.Article in journal (Refereed) Published
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 (TGFbeta) 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 TGFbeta 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 TGFbeta1/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, TGFbeta1/Smad3 suppresses BRCA1-dependent DNA repair in response to a DNA damaging agent.
Place, publisher, year, edition, pages
2005. Vol. 24, no 14, 2289-2297 p.
Blotting; Western, Cell Line, Cell Survival, DNA Damage, DNA Repair/*physiology, DNA-Binding Proteins/*physiology, Genes; BRCA1, Humans, Immunohistochemistry, Immunoprecipitation, Research Support; Non-U.S. Gov't, Trans-Activators/*physiology, Transcription; Genetic, Transforming Growth Factor beta/*physiology
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-72687DOI: 10.1038/sj.onc.1208443ISI: 000227877400002PubMedID: 15735739OAI: oai:DiVA.org:uu-72687DiVA: diva2:100598