Inherited mutations in the gene encoding BRCA2 are associated with a predisposition to early-onset breast and ovarian cancers. The underlying basis of the tumorigenesis is thought to be linked to defects in homologous recombination which results in radiation sensitivity, mutation, and loss of genome stability. We seek to understand the molecular mechanism of BRCA2 through analysis of its ortholog Brti2 in a model microbial system, Ustilago maydis that is amenable to molecular genetic manipulations. The powerful attributes of this system open the way for understanding BRCA2's molecular mechanism through avenues not yet approachable in the higher eukaryotic systems. We plan 3 lines of attack. First, we will dissect Brh2 by molecular and genetic means to define and map its functional domains. Second, we will investigate how Brh2's interaction with the Rad51 recombinase is regulated by Dss1, a small associated protein that serves as a necessary cofactor. Third, we will use genetic methods to investigate Brh2's network of interacting genes. Relevance: It was previously thought that BRCA2 was a gene found only in mammals, but recently it has become apparent that BRCA2 is conserved and is present in many life forms up and down the evolutionary tree. U. maydis is a laboratory microbe in which the BRCA2 system is recapitulated at the molecular level and thus offers a unique opportunity for experimentation on BRCA2 to a degree as yet unattainable in mammalian systems. Understanding the molecular mechanism of BRCA2, as for any gene implicated in cancer, contributes in the most fundamental way to a knowledge base illuminating the gene's action. The assembly of such knowledge is the real precursor to breast cancer therapy and cure.
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| Kojic, Milorad; Holloman, William K (2012) Brh2 domain function distinguished by differential cellular responses to DNA damage and replication stress. Mol Microbiol 83:351-61 |
| Zhou, Qingwen; Kojic, Milorad; Holloman, William K (2012) Dss1 release activates DNA binding potential in Brh2. Biochemistry 51:9137-46 |
| Holloman, William K (2011) Unraveling the mechanism of BRCA2 in homologous recombination. Nat Struct Mol Biol 18:748-54 |
| Kojic, Milorad; Zhou, Qingwen; Fan, Jie et al. (2011) Mutational analysis of Brh2 reveals requirements for compensating mediator functions. Mol Microbiol 79:180-91 |
| de Sena-Tomás, Carmen; Fernández-Álvarez, Alfonso; Holloman, William K et al. (2011) The DNA damage response signaling cascade regulates proliferation of the phytopathogenic fungus Ustilago maydis in planta. Plant Cell 23:1654-65 |
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