Genomic maintenance systems are important determinants of longevity in all species. In mammals, DNA damage and faulty repair are major causes of cancer and non-cancer aging phenotypes. Normal cells respond to unrepaired DNA damage by apoptosis or cellular senescence, which suppress tumorigenesis but may also contribute to age-related pathology. WRN and BLM are related members of the mammalian RECQ-like family of DNA helicases. Current evidence suggests that both proteins participate in repairing DNA damage, among other possible functions. The phenotypes of humans deficient in these helicases suggest that both proteins prevent certain age-related diseases, including cancer. Werner syndrome (WS) and Bloom syndrome (BS) are caused by a deficiency in WRN and BLM, respectively. WS and BS share several features, but also show striking differences, the bases for which are largely unknown. Our overall goal is to better understand the cellular functions of the human WRN and BLM proteins. We propose to focus primarily on human cells, and determine how WRN and BLM are regulated, and how they regulate responses to DNA damage. We propose to determine effects of wild type and mutant WRN and BLM proteins on the senescence and apoptotic responses, telomere dynamics and genomic integrity of human cells. We will also determine how selected damage-sensing protein kinases regulate the subnuclear localization of WRN and BLM and its response to DNA damage. Our studies will provide important insights into how WRN and BLM postpone the development of aging phenotypes and the development of cancer in humans.
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