A genomewide screen for suppressors of Alu-mediated rearrangements reveals a role for PIF1.

PloS One
Karen M ChisholmP Welcsh

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...Continue Reading

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Datasets Mentioned

BETA
L78833
58500–58798

Methods Mentioned

BETA
electrophoresis
protein assay

Software Mentioned

PredictProtein
MacVector
SIFT
Polyphen
PSIPRED
Sequencherâ¢
BLASTp
Sequencing Analysis
UCSC Genome Browser

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