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Incidence of DSS1 Mutations in High Risk Breast Cancer Families
BRCA1 and BRCA2 are the products of the two major inherited breast cancer susceptibility genes. Both appear to function in repair of DNA by sequence homology-directed recombination. Although the role of BRCA1 in this process is not very well defined, BRCA2 is known to regulate the Rad51 recombinase, which provides the essential catalytic activity required for DNA strand exchange during recombinational repair. BRCA2 in turn is regulated by DSS1, a small protein that associates strongly with the C-terminal DNA binding domain of BRCA2. The nature of BRCA2’s regulation by DSS1 is unknown, but evidence accumulating in the model microbial system Ustilago maydis, in which the BRCA2 paradigm is recapitulated, indicates that DSS1 serves as a positive activator as well as a governor of BRCA2 checking its capacity to promote recombination. The importance of DSS1 as a player in the recombinational repair system is well on the way to being appreciated, but to date there are no studies addressing the possibility that mutations in DSS1 could contribute to increased susceptibility to breast cancer. Here, we propose to examine the DSS1 gene from a cohort of about 80 individuals at high risk for breast cancer who are already known to have no mutation in BRCA1 or BRCA2. The DNA sequence of the three DSS1 exons will be determined from DNA samples prepared from blood of these individuals. If any alterations that give rise to chain-terminating or missense mutations are identified, the corresponding mutations will be constructed in the U. maydis DSS1 gene, and the alleles will then be tested for biological activity after introducing them into a dss1 null mutant. Any allele found that fails to complement the radiation sensitivity of dss1 would be considered evidence in support of DSS1 as an additional heritable gene predisposing to breast cancer.
BRCA1 and BRCA2 are two genes known to be involved in the inherited form of breast cancer susceptibility. The proteins encoded by both genes appear to play an important role in maintaining the integrity of the genetic material by repairing DNA that has been damaged or broken during the course of ordinary metabolism in cell growth. BRCA1 seems to be particularly complex in its action in the cell and there is a good deal of confusion about exactly what it does. More is understood about how BRCA2 works and in particular some of the mechanistic details of exactly how it works at the molecular level are beginning to emerge. One interesting recent finding is that BRCA2 associates strongly with another protein called DSS1. The significance of this association was unknown when it was originally discovered. But just recently it was found by examining the corresponding protein in a model microbial system with a BRCA2 similar to that in humans, that DSS1 is absolutely essential for BRCA2 to perform its job in repairing DNA. In other words, DSS1 is a switch that turns on BRCA2. Since there is good reason to think that there are additional genes that play a role in inherited breast cancer susceptibility, it is entirely possible that DSS1 could be one of them. Our aim in this proposal is to find out if this is true. Here we propose to examine the DSS1 gene in DNA samples collected from individuals at high risk for breast cancer who have already been found to have normal BRCA1 and BRCA2 genes. We will look for mutations in the DSS1 gene from about 80 of these individuals. If any are found, they will be tested for biological function by introducing them into the model microbial system to see if they are impaired in their ability to activate BRCA2. Thus, the microbial system will be able to confirm whether a particular DSS1 mutation is merely a variant with no particular significance, as is often the case with human genes, or whether that mutation has functional consequences. Obviously, identification of a new gene involved in hereditary breast cancer predisposition could have far-reaching effects on screening and treatment.