Mechanisms of DNA Motor Proteins in Genome Maintenance

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DESCRIPTION (provided by applicant): The long-term goals are to understand the mechanisms by which DNA-binding motor proteins act in the promotion and regulation of homologous recombination (HR). Importantly, many of these DNA motor proteins are indispensable for cancer avoidance in mammals. For instance, mutations in the motor proteins BLM and RECQ5 lead to aberrant recombination events and are associated with tumorigenesis, and mutations in Rad54 and Rad54B are found in a variety of tumor types. Understanding the properties of these motor proteins, and delineating their roles in genome maintenance, will be essential for revealing the molecular basis for defects that produce the disease phenotypes. However, the mechanistic details of how these proteins function have remained largely elusive. Our hypothesis is that DNA motor proteins contribute to genome maintenance through their ability to translocate along DNA and remove proteins from DNA, and that their functions are mediated through specific interactions with other DNA repair factors. To test this hypothesis we will take a multidisciplinary approach that integrates our distinct areas of expertise in genetics (H. Klein), biochemistry (P. Sung) and single-molecule biophysics (E. Greene) to conduct a detailed analysis of the S. cerevisiae DNA motor proteins Rad54, Rdh54, Tid4, and Srs2. Each of these proteins participates in different aspects of DNA double-strand break (DSB) repair through HR. Working together, our three laboratories are well positioned to decipher the mechanisms of these motor proteins and provide a valuable experimental framework for understanding the genom maintenance and tumor suppression roles of their mammalian counterparts. PUBLIC HEALTH RELEVANCE: Cancers are characterized by genomic instability and rearrangements, which are promoted by errors in replication, repair and recombination. The proposed studies will reveal new genes and mechanisms for promoting genome maintenance in the face of constant DNA damage that occurs every cell division.