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  • Original Paper
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A single mutated BRCA1 allele leads to impaired fidelity of double strand break end-joining

Oncogene volume 21, pages 1401–1410 (2002)Cite this article

Abstract

Heterozygosity for mutations in the BRCA1 gene in humans confers high risk for developing breast cancer, but a biochemical basis for this phenotype has not yet been determined. Evidence has accumulated implicating BRCA1, in the maintenance of genomic integrity and the protection of cells against DNA double strand breaks (DSB). Here we present evidence that human cells heterozygous for BRCA1 mutations exhibit impaired DNA end-joining, which is the major DSB repair pathway in mammalian somatic cells. Using an in vivo host cell end-joining assay, we observed that the fidelity of DNA end-joining is strongly reduced in three BRCA1+/− cell lines in comparison to two control cell lines. Moreover, cell-free BRCA1+/− extracts are unable to promote accurate DNA end-joining in an in vitro reaction. The steady-state level of the wild type BRCA1 protein was significantly lower than the 50% expected in BRCA1+/− cells and thus may underlie the observed end-joining defect. Together, these data strongly suggest that BRCA1 is necessary for faithful rejoining of broken DNA ends and that a single mutated BRCA1 allele is sufficient to impair this process. This defect will compromise genomic stability in BRCA1 germ-line mutation carriers, triggering the genetic changes necessary for the initiation of neoplastic transformation.

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Acknowledgements

We specially thank Dr SC West (Imperial Cancer Research Fund, Clare Hall Laboratories, UK) and Dr N Doyen (URA1960 CNRS, Institut Pasteur, France) for their critical comments and valuable suggestions and Dr J Couturier and D Rouillard for their contribution. We are grateful to Dr E Moustacchi and Dr G Almouzni for helpful discussions and critical readings of the manuscript. This work is supported by the Centre National pour la Recherche Scientifique, and grants from Association pour la Recherche sur le Cancer, Commission of European Community and Ministére de l'Education Nationale et de la Recherche. J Smith was a recipient of a Fellowship from, Ligue Nationale Française contre le Cancer and Institut Curie-Research Division. C Baldeyron, C Jacquemont and S Gad were recipient of Fellowships from the Ministère de l'Education Nationale et de la Recherche.

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Author notes

  1. Emilie Jacquemin and Julianne Smith: C Baldeyron and E Jacquemin equally contributed to the work

Authors and Affiliations

  1. UMR 218 du CNRS, Institut Curie, Section de Recherche, Paris, 75248, cedex05, France

    Céline Baldeyron, Emilie Jacquemin, Julianne Smith, Céline Jacquemont, Isabelle De Oliveira & Dora Papadopoulo

  2. Service de Génétique Oncologique, Institut Curie, Section Médicale, Paris, 75248, cedex05, France

    Sophie Gad & Dominique Stoppa-Lyonnet

  3. UMR 1599 du CNRS Institut Gustave-Roussy, cedex, 94805, Villejuif, France

    Jean Feunteun

Authors
  1. Céline Baldeyron
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  2. Emilie Jacquemin
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  9. Dora Papadopoulo
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Correspondence to Dora Papadopoulo.

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Baldeyron, C., Jacquemin, E., Smith, J. et al. A single mutated BRCA1 allele leads to impaired fidelity of double strand break end-joining. Oncogene 21, 1401–1410 (2002). https://doi.org/10.1038/sj.onc.1205200

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