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Nuclear–cytoplasmic translocation of BARD1 is linked to its apoptotic activity

Oncogene volume 23, pages 3509–3520 (2004)Cite this article

Abstract

The tumor suppressor protein BARD1 plays a dual role in response to genotoxic stress: DNA repair as a BARD1–BRCA1 heterodimer and induction of apoptosis in a BRCA1-independent manner. We have constructed a series of BARD1 deletion mutants and analysed their cellular distribution and capacity to induce apoptosis. As opposed to previous studies suggesting an exclusively nuclear localization of BARD1, we found, both in tissues and cell cultures, nuclear and cytoplasmic localization of BARD1. Enhanced cytoplasmic localization of BARD1, as well as appearance of a 67 kDa C-terminal proteolytic cleavage product, coincided with apoptosis. BARD1 translocates to the nucleus independently of BRCA1. For recruitment to nuclear dots, however, the BRCA1-interacting RING finger domain is required but not sufficient. Protein levels of N-terminal RING finger deletion mutants were much higher than those of full-length BARD1, despite comparable mRNA levels, suggesting that the N-terminal region comprising the RING finger is important for BARD1 degradation. Sequences required for apoptosis induction were mapped between the ankyrin repeats and the BRCT domains coinciding with two known cancer-associated missense mutations. We suggest that nuclear and cytoplasmic localization of BARD1 reflect its dual function and that the increased cytoplasmic localization of BARD1 is associated with apoptosis.

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Acknowledgements

This work was supported by Swiss National Science Foundation grant to IIF and KHK, and Johnson & Johnson and AETAS awards to IIF. We are grateful to Dr Gilbert LeNoir and Dr Anne Vincent for the generous gift of the BRCA1 antibody, Dr Monica Sauer for discussing with us unpublished observations, Dr Wai-Choi Leung for critical comments on the manuscript, and Aurélie Caillon for excellent technical support.

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Authors and Affiliations

  1. Department of Geriatrics, Biology of Aging Laboratory, University of Geneva, Geneva, 1225, Switzerland

    Charles Edward Jefford, Anis Feki, Karl-Heinz Krause & Irmgard Irminger-Finger

  2. Institut de Biologie, INSERM U419, 9 quai Moncousu, Nantes, Cédex 03, 44035, France

    Jean Harb

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  1. Charles Edward Jefford
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Correspondence to Irmgard Irminger-Finger.

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Jefford, C., Feki, A., Harb, J. et al. Nuclear–cytoplasmic translocation of BARD1 is linked to its apoptotic activity. Oncogene 23, 3509–3520 (2004). https://doi.org/10.1038/sj.onc.1207427

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