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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA077852-14
Application #
8375343
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
14
Fiscal Year
2012
Total Cost
$311,068
Indirect Cost
$75,890
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Welcsh, Piri; Kehrli, Keffy; Lazarchuk, Pavlo et al. (2016) Application of the microfluidic-assisted replication track analysis to measure DNA repair in human and mouse cells. Methods 108:99-110
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
Loeb, Lawrence A (2016) Human Cancers Express a Mutator Phenotype: Hypothesis, Origin, and Consequences. Cancer Res 76:2057-9
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
Bosch, Linda J W; Luo, Yanxin; Lao, Victoria V et al. (2016) WRN Promoter CpG Island Hypermethylation Does Not Predict More Favorable Outcomes for Patients with Metastatic Colorectal Cancer Treated with Irinotecan-Based Therapy. Clin Cancer Res 22:4612-22
Cohen, Stacey A; Wu, Chen; Yu, Ming et al. (2016) Evaluation of CpG Island Methylator Phenotype as a Biomarker in Colorectal Cancer Treated With Adjuvant Oxaliplatin. Clin Colorectal Cancer 15:164-9
Ahn, Eun Hyun; Lee, Seung Hyuk; Kim, Joon Yup et al. (2016) Decreased Mitochondrial Mutagenesis during Transformation of Human Breast Stem Cells into Tumorigenic Cells. Cancer Res 76:4569-78
Tang, Weiliang; Robles, Ana I; Beyer, Richard P et al. (2016) The Werner syndrome RECQ helicase targets G4 DNA in human cells to modulate transcription. Hum Mol Genet 25:2060-2069
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
Kehrli, Keffy; Phelps, Michael; Lazarchuk, Pavlo et al. (2016) Class I Histone Deacetylase HDAC1 and WRN RECQ Helicase Contribute Additively to Protect Replication Forks upon Hydroxyurea-induced Arrest. J Biol Chem 291:24487-24503

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