title: A genomewide screen for suppressors of Alu-mediated rearrangements reveals a role for PIF1.
abstract: 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.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Chisholm
authors.forename: Sarah D
authors.initials: SD
authors.lastname: Aubert
authors.forename: Krister P
authors.initials: KP
authors.lastname: Freese
authors.forename: Virginia A
authors.initials: VA
authors.lastname: Zakian
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.forename: Piri L
authors.initials: PL
authors.lastname: Welcsh
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics* / Q000502:physiology; D005190:Family; D005260:Female; D015321:Gene Rearrangement; D052138:Genes, Neoplasm; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D016681:Genome, Fungal; D006801:Humans; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA; D015003:Yeasts
chemical_list: D029702:Schizosaccharomyces pombe Proteins; D004265:DNA Helicases; C468287:Pfh1 protein, S pombe; C508765:PIF1 protein, human