Project 1: Biochemistry The RecQ family of DNA helicases Includes the Werner syndrome (WS) protein WRN. Mutations in WRN are associated with genetic instability and age-related diseases, including an increase in specific cancers. Our long-term objective is to characterize the biochemical properties and functions of WRN, and to illuminate how they contribute to the maintenance of genomic integrity and avoidance of cancer. Our overall hypothesis is that WRN prevents collapse of replication forks by facilitating DNA synthesis past sites of covalent damage and by unwinding alternative secondary structures. We have the following Specific Aims: [1) To assess the role of WRN in facilitating replication of unrepaired DNA damage and alternate DNA structures by translesion (""""""""errorprone"""""""") DNA polymerases and by DNA polymerase 8 (Pol 8), in collaboration with Project 2; [2] To delineate the interactions of WRN with telomerase and telomeric DNA,. in collaboration with Project 3 and Dr. Jack Griffith at the University of North Carolina;[3) To determine if reduction in WRN content results in a decrease in random mutations throughout the genome together with an increase in deletion mutations;. [4) To characterize the phenotypic manifestations of single nucleotide polymorphisms that? greatly diminish WRN helicase activity, in collaboration with Core A and Dr. Gerardo Jimenez-Sanchez at the National Institute of Genomic Medicine, Mexico. These proposed studies, in concert with those in the other Projects and Cores, will contribute to our understanding of the roles of RecQ helicases in human biology and cancer.

Public Health Relevance

The Werner syndrome protein, WRN, is required to safeguard the integrity of DNA and to avoid age-related diseases including cancer. Our proposed work on the biochemical properties and functions of WRN will further our knowledge of the mechanisms by which this disease-associated enzyme maintains the health of human cells and human populations.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-GRB-S)
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University of Washington
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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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