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.
| Orozco, Javier I J; Knijnenburg, Theo A; Manughian-Peter, Ayla O et al. (2018) Epigenetic profiling for the molecular classification of metastatic brain tumors. Nat Commun 9:4627 |
| Schmitt, Michael W; Pritchard, Justin R; Leighow, Scott M et al. (2018) Single-Molecule Sequencing Reveals Patterns of Preexisting Drug Resistance That Suggest Treatment Strategies in Philadelphia-Positive Leukemias. Clin Cancer Res 24:5321-5334 |
| Mikheev, Andrei M; Mikheeva, Svetlana A; Severs, Liza J et al. (2018) Targeting TWIST1 through loss of function inhibits tumorigenicity of human glioblastoma. Mol Oncol 12:1188-1202 |
| Lee, Su-In; Celik, Safiye; Logsdon, Benjamin A et al. (2018) A machine learning approach to integrate big data for precision medicine in acute myeloid leukemia. Nat Commun 9:42 |
| Salk, Jesse J; Schmitt, Michael W; Loeb, Lawrence A (2018) Enhancing the accuracy of next-generation sequencing for detecting rare and subclonal mutations. Nat Rev Genet 19:269-285 |
| Davis, Luther; Zhang, Yinbo; Maizels, Nancy (2018) Assaying Repair at DNA Nicks. Methods Enzymol 601:71-89 |
| Yu, Ming; Heinzerling, Tai J; Grady, William M (2018) DNA Methylation Analysis Using Droplet Digital PCR. Methods Mol Biol 1768:363-383 |
| Knijnenburg, Theo A; Wang, Linghua; Zimmermann, Michael T et al. (2018) Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas. Cell Rep 23:239-254.e6 |
| 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 |
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