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.
Highlights
Alu elements account for more than 10% of the human genome [1] and provide abundant opportunities for unequal homologous recombination both intrachromosomally, resulting in deletion or duplication of exons in a gene, and interchromosomally, causing more complex chromosomal abnormalities
At least 81 large genomic rearrangements in BRCA1 have been identified in high-risk breast cancer families, the majority of which are deletions ranging in size from a few hundred base pairs, to tens of kilobases
Knudson’s model would have predicted that in at least a proportion of these cases, BRCA1 is inactivated by a somatically acquired mutation. Contradicting this hypothesis is the observation that somatic BRCA1 mutations are exceedingly rare in sporadic carcinomas
Summary
Alu elements account for more than 10% of the human genome [1] and provide abundant opportunities for unequal homologous recombination both intrachromosomally, resulting in deletion or duplication of exons in a gene, and interchromosomally, causing more complex chromosomal abnormalities. It is not surprising that unequal homologous recombination between Alu repeats contributes to a significant proportion of human genetic disease [2]. At least 81 large genomic rearrangements in BRCA1 have been identified in high-risk breast cancer families, the majority of which are deletions ranging in size from a few hundred base pairs, to tens of kilobases. Large genomic rearrangements account for up to 12% of all novel BRCA1 mutations identified in high-risk breast cancer families [5]
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