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Cells Expressing Murine RAD52 Splice Variants Favor Sister Chromatid Repair

Peter H. Thorpe,¹ Vanessa A. Marrero,¹ Margaret H. Savitzky,^1, Ivana Sunjevaric,¹ Tom C. Freeman,^2, and Rodney Rothstein^1*

Department of Genetics and Development, Columbia University Medical Center, 701 West 168th St., New York, New York 10032,¹ Gene Expression Group, Sanger Centre, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom²

Received 11 July 2005/ Returned for modification 2 February 2006/ Accepted 24 February 2006

The RAD52 gene is essential for homologous recombination in the yeast Saccharomyces cerevisiae. RAD52 is the archetype in an epistasis group of genes essential for DNA damage repair. By catalyzing the replacement of replication protein A with Rad51 on single-stranded DNA, Rad52 likely promotes strand invasion of a double-stranded DNA molecule by single-stranded DNA. Although the sequence and in vitro functions of mammalian RAD52 are conserved with those of yeast, one difference is the presence of introns and consequent splicing of the mammalian RAD52 pre-mRNA. We identified two novel splice variants from the RAD52 gene that are expressed in adult mouse tissues. Expression of these splice variants in tissue culture cells elevates the frequency of recombination that uses a sister chromatid template. To characterize this dominant phenotype further, the RAD52 gene from the yeast Saccharomyces cerevisiae was truncated to model the mammalian splice variants. The same dominant sister chromatid recombination phenotype seen in mammalian cells was also observed in yeast. Furthermore, repair from a homologous chromatid is reduced in yeast, implying that the choice of alternative repair pathways may be controlled by these variants. In addition, a dominant DNA repair defect induced by one of the variants in yeast is suppressed by overexpression of RAD51, suggesting that the Rad51-Rad52 interaction is impaired.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: Thomas A. Edison High School, 165-65 84th Avenue, Jamaica, NY 11432.

Present address: Scottish Centre for Genomic Technology and Informatics, University of Edinburgh Medical School, Chancellor's Building, Edinburgh EH16 4SB, United Kingdom.

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