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TGFβ1/Smad3 counteracts BRCA1-dependent repair of DNA damage

Oncogene volume 24, pages 2289–2297 (2005)Cite this article

Abstract

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-β (TGFβ) 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 TGFβ 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 TGFβ1/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, TGFβ1/Smad3 suppresses BRCA1-dependent DNA repair in response to a DNA damaging agent.

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Acknowledgements

We are grateful to Hiroyuki Iwahana, Taras Stasyk for comments, Vasyl Lukiyanchuk for help and advises, Mary Helen Barcellos-Hoff for discussions, Toru Ouchi, Dou Liu, Stephen Elledge, Kohei Miyazono, Didier Marot, Napoleone Ferrara and Johan Ericsson for reagents, and Yevhen Filjak for primary amplification of the BRCA1 virus. This work was supported in part by grants from the Royal Swedish Academy of Sciences, the INSERM/MFR/VR, the EU program on angiogenesis (T-ANGIOVASC), the Swedish Cancer Society, and from the Swedish Research Council to Serhiy Souchelnytskyi.

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Author notes

  1. Anna Dubrovska, Takashi Kanamoto and Marta Lomnytska: These authors contributed equally to this work

Authors and Affiliations

  1. Ludwig Institute for Cancer Research, Biomedical Center, Box 595, SE-751 24, Uppsala, Sweden

    Anna Dubrovska, Takashi Kanamoto, Marta Lomnytska, Carl-Henrik Heldin & Serhiy Souchelnytskyi

  2. Department of Ophthalmology and Visual Science, Hiroshima University, Graduate School of Biomedical Sciences, 1-2-3 Kasumi, Minani-ku, Hiroshima, 734-8551, Japan

    Takashi Kanamoto

  3. Department of Oncology and Medical Radiology, Lviv National Medical University, Hasheka 2A, UA-79031, Lviv, Ukraine

    Marta Lomnytska & Natalya Volodko

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  1. Anna Dubrovska
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  2. Takashi Kanamoto
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  6. Serhiy Souchelnytskyi
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Correspondence to Serhiy Souchelnytskyi.

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Dubrovska, A., Kanamoto, T., Lomnytska, M. et al. TGFβ1/Smad3 counteracts BRCA1-dependent repair of DNA damage. Oncogene 24, 2289–2297 (2005). https://doi.org/10.1038/sj.onc.1208443

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