Understanding the role of RAD51C complexes in recombination and repair

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DESCRIPTION (provided by applicant): A functional machinery to repair DNA breaks is required for maintaining genome integrity and preventing tumourigenesis. In order to gain mechanistic insights into the complex DNA break repair network in mammalian cells, it is critical to identify novel factors that are required for each steps of the repair event. Equally, we need to define the roles of the known DNA break repair proteins, such as the RAD51 paralogs, as mutations in these proteins have been associated with increased cancer risks and decreased survival of cancer patients after cytotoxic therapies. Previously, we identified two of the RAD51 paralogs, RAD51C and XRCC3, as the essential components of Holliday junction resolvasome, a complex required for separate linked chromosomes during DNA break repair. This finding not only indicates a novel role of RAD51C and XRCC3 at the late stage of recombination but also in processing stalled replication forks. In addition, our studies also suggest functional interactions of the RAD51C complexes with ERCC1 and the RECQ helicases, both of which were important for processing recombination intermediates and stalled replication forks. Our goal is to define these unique functions of RAD51C complexes in recombinational repair that may explain their importance in genome maintenance and development. The Specific Aims are: (1) Identification and characterization of novel RAD51C-interacting proteins in recombinational repair. (2) Analysis of the functional relationship between RAD51C complexes and ERCC1. (3) Biochemical analysis of the functional relationship between RAD51C complexes and the RECQ proteins. Public Health Relevance: Our research goal is to understand the complex mechanisms that repair damaged DNA, because loss of genome integrity can lead to cell transformation and cancer development. Our detailed knowledge of DNA repair proteins is also crucial for developing drugs that can be used in combination with radiotherapy or chemotherapy, since the inhibition of DNA damage repair in tumor cells would make them more susceptible to therapy, thus allowing more efficient treatment of cancer.