The goals of this Program are to delineate in vivo functions of the human RecQ helicase proteins, and to understand how loss of RecQ helicase function leads to genetic instability, an elevated risk of cancer and selective sensitivity to cancer chemotherapeutic agents. Our long term goal is to use new information on the human RecQ proteins to modify or limit disease risk or progression, and to devise novel, targeted anticancer therapies. In order to achieve these goals, we have developed an integrated research Program of 4 Projects and 2 Cores focused on three Experimental Aims. Our revised Aims are:
Aim 1 : to determine molecular and mechanistic aspects of RecQ helicase function in human cells;
Aim 2 : to determine how loss of RecQ helicase function promotes genetic instability, limits cell proliferation and leads to heightened sensitivity to cancer chemotherapeutic agents including topoisomerase I inhibitors and DNA cross linking drugs;
and Aim 3 : to determine how RecQ helicases can be further developed as biomarkers and targets to modify cancer risk and to improve the response or devise new approaches to chemotherapy of human colorectal and breast carcinomas. This revised Renewal incorporates a newly developed and substantially expanded research emphasis on human tumors, patient cohorts and genetically defined populations. The Program as a whole reflects a growing recognition of the role for RecQ helicases in human biology and disease, most notably in cancer biology and the response to cancer chemotherapy. Thus the proposed research will have substantial basic science, clinical and translational potential. We plan to fully develop these opportunities in the proposed research.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-GRB-S (M1))
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Okano, Paul
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University of Washington
Schools of Medicine
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Reid-Bayliss, Kate S; Loeb, Lawrence A (2017) Accurate RNA consensus sequencing for high-fidelity detection of transcriptional mutagenesis-induced epimutations. Proc Natl Acad Sci U S A 114:9415-9420
Kamath-Loeb, Ashwini S; Zavala-van Rankin, Diego G; Flores-Morales, Jeny et al. (2017) Homozygosity for the WRN Helicase-Inactivating Variant, R834C, does not confer a Werner syndrome clinical phenotype. Sci Rep 7:44081
Oshima, Junko; Sidorova, Julia M; Monnat Jr, Raymond J (2017) Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions. Ageing Res Rev 33:105-114
Yuan, Zixu; Baker, Kelsey; Redman, Mary W et al. (2017) Dynamic plasma microRNAs are biomarkers for prognosis and early detection of recurrence in colorectal cancer. Br J Cancer 117:1202-1210
Poole, William; Leinonen, Kalle; Shmulevich, Ilya et al. (2017) Multiscale mutation clustering algorithm identifies pan-cancer mutational clusters associated with pathway-level changes in gene expression. PLoS Comput Biol 13:e1005347
Fu, Wenqing; Ligabue, Alessio; Rogers, Kai J et al. (2017) Human RECQ Helicase Pathogenic Variants, Population Variation and ""Missing"" Diseases. Hum Mutat 38:193-203
Beckman, Robert A; Loeb, Lawrence A (2017) Evolutionary dynamics and significance of multiple subclonal mutations in cancer. DNA Repair (Amst) 56:7-15
Fox, Edward J; Salk, Jesse J; Loeb, Lawrence A (2016) Exploring the implications of distinct mutational signatures and mutation rates in aging and cancer. Genome Med 8:30
Tokita, Mari; Kennedy, Scott R; Risques, Rosa Ana et al. (2016) Werner syndrome through the lens of tissue and tumour genomics. Sci Rep 6:32038
Reid-Bayliss, Kate S; Arron, Sarah T; Loeb, Lawrence A et al. (2016) Why Cockayne syndrome patients do not get cancer despite their DNA repair deficiency. Proc Natl Acad Sci U S A 113:10151-6

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