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Human Molecular Genetics Advance Access published online on February 27, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl037
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received January 12, 2006
Revised February 16, 2006
Accepted February 16, 2006

Article

Mitotic defects in XRCC3 variants T241M and D213N and their relation to cancer susceptibility

Anna Renglin Lindh 1, Saeed Rafii 2, Niklas Schultz 1, Angela Cox 2, and Thomas Helleday 3 *

1 Department of Genetics, Microbiology and Toxicology, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden
2 The Institute for Cancer Studies, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK
3 Department of Genetics, Microbiology and Toxicology, Arrhenius Laboratory, Stockholm University, Svante Arrheniusv. 16-18, S-106 91 Stockholm, Sweden; The Institute for Cancer Studies, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK

* To whom correspondence should be addressed.
Thomas Helleday, E-mail: helleday{at}gmt.su.se


  Abstract

The XRCC3 variant T241M, but not D213N, has been reported to be associated with an increased risk of some cancers. XRCC3 is one out of five RAD51 paralogs and is involved in homologous recombination, as are the BRCA1 and BRCA2 proteins. However, in contrast to mutations in BRCA1 and BRCA2, the XRCC3T241M protein is proficient in homologous recombination and reverts sensitivity to mitomycin C found in XRCC3 deficient cells, while XRCC3D213N is defective in homologous recombination. Here, we report that both the XRCC3 D213N and T241M alleles are associated with an increase in centrosome number and binucleated cells. However, only the D213N allele give an increase in spontaneous levels of apoptosis. We suggest that the inability of XRCC3 T241M to apoptotically eliminate aberrant cells with mitotic defects could increase cancer susceptibility in individuals carrying this variant. In contrast, cells carrying the XRCC3 D213N variant are able to eliminate aberrant cells by apoptosis, and consistent with this observation, this variant does not seem to be associated with cancer susceptibility.


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