Journal Article

A tumour-derived mutant allele of XRCC2 preferentially suppresses homologous recombination at DNA replication forks

Atul Mohindra, Emma Bolderson, Jason Stone, Michael Wells, Thomas Helleday and Mark Meuth

in Human Molecular Genetics

Volume 13, issue 2, pages 203-212
Published in print January 2004 | ISSN: 0964-6906
Published online November 2003 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddh022
A tumour-derived mutant allele of XRCC2 preferentially suppresses homologous recombination at DNA replication forks

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Homologous recombination repair (HRR) is required for both the repair of DNA double strand breaks (DSBs) and the maintenance of the integrity of DNA replication forks. To determine the effect of a mutant allele of the RAD51 paralog XRCC2 (342delT) found in an HRR-defective tumour cell line, 342delT was introduced into HRR proficient cells containing a recombination reporter substrate. In one set of transfectants, expression of 342delT conferred sensitivity to thymidine and mitomycin C and suppressed HRR induced at the recombination reporter by thymidine but not by DSBs. In a second set of transfectants, the expression of 342delT was accompanied by a decreased level of the full-length XRCC2. These cells were defective in the induction of HRR by either thymidine or DSBs. Thus 342delT suppresses recombination induced by thymidine in a dominant negative manner while recombination induced by DSBs appears to depend upon the level of XRCC2 as well as the expression of the mutant XRCC2 allele. These results suggest that HRR pathways responding to stalled replication forks or DSBs are genetically distinguishable. They further suggest a critical role for XRCC2 in HRR at replication forks, possibly in the loading of RAD51 onto gapped DNA.

Journal Article.  6354 words.  Illustrated.

Subjects: Genetics and Genomics

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