RAD51 is an important component of double-stranded DNA-repair mechanisms that interacts with both BRCA1 and BRCA2. A single-nucleotide polymorphism (SNP) in the 5' untranslated region (UTR) of RAD51, 135G-->C, has been suggested as a possible modifier of breast cancer risk in BRCA1 and BRCA2 mutation carriers. We pooled genotype data for 8,512 female mutation carriers from 19 studies for the RAD51 135G-->C SNP. We found evidence of an increased breast cancer risk in CC homozygotes (hazard ratio [HR] 1.92 [95% confidence interval {CI} 1.25-2.94) but not in heterozygotes (HR 0.95 [95% CI 0.83-1.07]; P=.002, by heterogeneity test with 2 degrees of freedom [df]). When BRCA1 and BRCA2 mutation carriers were analyzed separately, the increased risk was statistically significant only among BRCA2 mutation carriers, in whom we observed HRs of 1.17 (95% CI 0.91-1.51) among heterozygotes and 3.18 (95% CI 1.39-7.27) among rare homozygotes (P=.0007, by heterogeneity test with 2 df). In addition, we determined that the 135G-->C variant affects RAD51 splicing within the 5' UTR. Thus, 135G-->C may modify the risk of breast cancer in BRCA2 mutation carriers by altering the expression of RAD51. RAD51 is the first gene to be reliably identified as a modifier of risk among BRCA1/2 mutation carriers.
The AURKA oncogene is associated with abnormal chromosome segregation and aneuploidy and predisposition to cancer. Amplification of AURKA has been detected at higher frequency in tumors from BRCA1 and BRCA2 mutation carriers than in sporadic breast tumors, suggesting that overexpression of AURKA and inactivation of BRCA1 and BRCA2 cooperate during tumor development and progression. The F31I polymorphism in AURKA has been associated The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Cohesins are a group of proteins that function to mediate correct chromosome segregation, DNA repair and meiotic recombination. This report presents the amino acid sequence for the Schizosaccharomyces pombe cohesin Psc3 based on the translation of the cDNA sequence, showing that the protein is smaller than previously predicted. Interestingly, comparison of the amino acid and DNA coding sequences of Psc3 with fission yeast Rec11 meiotic region-specific recombination activator shows that both intron positioning within the genes and the amino-terminal half of the two proteins are highly conserved. We demonstrate that although the intergenic region upstream of the psc3+ start codon contains a consensus sequence for the cell-cycle regulatory MluI cell-cycle box, psc3+ transcription is not differentially regulated during the mitotic cell cycle. Finally, we demonstrate that an epitope-tagged version of Psc3 undergoes no major changes during the mitotic cell cycle. However, instead we identify at least three distinct isoforms of Psc3, suggesting that post-translational modification of Psc3 contributes to the regulation of cohesion function.
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