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Functional differences among BRCA1 missense mutations in the control of centrosome duplication

Oncogene volume 31, pages 799–804 (2012)Cite this article

Abstract

We analyzed the effects of 14 different missense mutations in the RING domain of BRCA1 on the function of the protein in the control of centrosome number in tissue culture cells. Whereas 2 of the 14 BRCA1 variant proteins were neutral in the centrosome duplication assay, missense mutations of zinc-coordinating residues (C24R, C27A, C39Y, H41F, C44F and C47G) and mutations encoding BRCA1 variants M18T and I42V resulted in BRCA1 proteins that caused centrosome amplification. BRCA1 variant proteins I21V, I31M, L52F and D67Y had an intermediate effect on centrosome duplication. In addition, one of the variants, L52F, caused a peculiar phenotype with amplified centrosomes but the centrioles remained paired. By comparison, other BRCA1 variants that caused centrosome amplification had clustering of supernumerary centrosomes with unpaired centrioles. This surprising phenotype suggests that the BRCA1 protein regulates two functions in the control of centrosome duplication: regulation of centrosome number and regulation of centriole pairing. The L52F is unusual as it is defective in only one of these processes. This study analyzes the function of BRCA1 missense mutations in the control of centrosome duplication, a critical step in the maintenance of genetic stability of mammary epithelial cells, and indicates a new function of BRCA1 in the control of centriole pairing.

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Acknowledgements

This work was supported by NIH Grant CA111480 (JDP).

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Authors and Affiliations

  1. Department of Biomedical Informatics and the Ohio State University Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA

    Z Kais & J D Parvin

  2. Department of Molecular Immunology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan

    N Chiba

  3. Department of Clinical Oncology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan

    C Ishioka

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  1. Z Kais
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  2. N Chiba
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  3. C Ishioka
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  4. J D Parvin
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Correspondence to J D Parvin.

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Supplementary Information accompanies the paper on the Oncogene website

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Kais, Z., Chiba, N., Ishioka, C. et al. Functional differences among BRCA1 missense mutations in the control of centrosome duplication. Oncogene 31, 799–804 (2012). https://doi.org/10.1038/onc.2011.271

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