Function of RecQ helicases in genome stability

National Institute On Aging

Investigators

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Abstract

DNA damage accumulates during life and is thought to contribute to aging and genomic instability. Therefore, defining those proteins and pathways that maintain genomic instability is critical in preventing aging and age-related degeneration. This project aims to understand what roles the five human RecQ helicases play in DNA repair and genomic stability. One major goal of our lab is to delineate the unique and complementary roles of the human RecQ helicases, with the expectation that we might fully explain each proteins function. Each RecQ possesses helicase and strand annealing activity as well as domains that confer unique functionality. We've demonstrated that all the RecQ helicases can be recruited to laser-induced double strand breaks (DSB), however the details of how each RecQ participates in DSB is less clear and therefore efforts are ongoing to dissect more precisely the role of each RecQ in DSB repair. Recently, we showed that RECQL4 interacts with Ku and further that loss of RECQL4 alters in vivo DSB repair efficiency. This expands the list of RecQs that interact with Ku to three: WRN, RECQL1 and RECQL4. The definitive role that RECQL4 plays in NHEJ and/or Alt-NHEJ is being explored. Another common interacting partner for the human RecQ proteins is PARP1. PARP1 is recruited early to DSB sites and orchestrates the recruitment and retention of many components of the DNA repair and DNA damage response network. We are investigating the mechanisms of interaction between RecQs and PARP1, mapping their domains of interaction and determining how significant the interactions are using survival assays. PARP1 inhibitors are used as anti-cancer therapies and since PARP1 is such a central play in the DNA damage response network, PARP inhibitors may alter RecQ protein functions. We are exploring these and other interaction partners to define the roles that RecQs play in DNA repair. In addition, our lab, in collaboration with others, continues to identify and characterize potential RecQ inhibitors. Thus far, inhibitors for both WRN and BLM have been identified, however both are suboptimal, thus we are continuing to screen for more optimized inhibitors.