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
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
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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
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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
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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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