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Alu -mediated rearrangement of tumor suppressor genes occurs frequently during carcinogenesis. In breast cancer, this mechanism contributes to loss of the wild-type  BRCA1  allele in inherited disease and to loss of heterozygosity in sporadic cancer. To identify genes required for suppression of  Alu -mediated recombination we performed a genomewide screen of a collection of 4672 yeast gene deletion mutants using a direct repeat recombination assay. The primary screen and subsequent analysis identified 12 candidate genes including  TSA ,  ELG1 , and  RRM3 , which are known to play a significant role in maintaining genomic stability. Genetic analysis of the corresponding human homologs was performed in sporadic breast tumors and in inherited  BRCA1 -associated carcinomas. Sequencing of these genes in high risk breast cancer families revealed a potential role for the helicase PIF1 in cancer predisposition. PIF1 variant L319P was identified in three breast cancer families; importantly, this variant, which is predicted to be functionally damaging, was not identified in a large series of controls nor has it been reported in either dbSNP or the 1000 Genomes Project. In  Schizosaccharomyces pombe ,  Pfh1  is required to maintain both mitochondrial and nuclear genomic integrity. Functional studies in yeast of human PIF1 L319P revealed that this variant cannot complement the essential functions of  Pfh1  in either the nucleus or mitochondria. Our results provide a global view of nonessential genes involved in suppressing  Alu -mediated recombination and implicate variation in  PIF1  in breast cancer predisposition.

A Genomewide Screen for Suppressors of Alu-Mediated Rearrangements Reveals a Role for PIF1