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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA077852-15
Application #
8494581
Study Section
Special Emphasis Panel (ZCA1-GRB-S (M1))
Program Officer
Okano, Paul
Project Start
2000-03-07
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
15
Fiscal Year
2013
Total Cost
$1,343,711
Indirect Cost
$426,157
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
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

Showing the most recent 10 out of 120 publications