Genetic instability is a hallmark of cancer. We have discovered that the hypoxic tumor microenvironment is an important cause of this instability. We have determined that hypoxic stress causes decreased expression at the transcriptional level of the DNA mismatch repair (MMR) factors, MLH1 and MSH2, and of the homology- dependent repair (HDR) factors, RAD51 and BRCA1. The MMR and HDR pathways are critical for maintaining genomic integrity. They play important roles in repairing environmental and endogenous DNA damage, and they influence the response of tumor cells to many cancer therapies, including ionizing radiation and alkylating and cross-linking agents. Mutations in MLH1 and MSH2 have been linked to hereditary colon cancer, while mutations in BRCA1 are associated with hereditary breast and ovarian cancers. In addition, MLH1 and BRCA1 levels are reduced in many sporadic cancers of these and other sites, a process associated with epigenetic silencing. Mechanistically, our initial studies have linked the Myc/Max network of transcription factors to the regulation of MLH1 and MSH2 expression and the E2F family of factors to the regulation of BRCA1 and RAD51. In this competing renewal application, we propose hypothesis-driven, mechanistic studies to elucidate the stress- response pathways that modulate the expression of these MMR and HDR repair genes. Using a battery of genetic and biochemical techniques, our work will focus on transcriptional regulation, epigenetic chromatin modification, and signal transduction events that occur in response to hypoxia and that may regulate DNA repair. We will also test specific hypotheses regarding the influence of hypoxia-induced changes in DNA repair on DNA damage signaling and on the efficacy of tailored therapeutic strategies that exploit these DNA repair changes. The altered regulation of DNA repair in response to cellular stresses such as hypoxia may be a key cause of genetic instability that promotes carcinogenesis and fosters tumor progression. At the same time, it may also offer the possibility of devising therapeutic strategies to which hypoxic cancer cells, but not normoxic, non- malignant cells, are especially susceptible. Hence, the proposed work will contribute to our understanding of basic cancer biology and may provide the basis for new approaches to cancer therapy.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Reinlib, Leslie J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
Cheng, Christopher J; Bahal, Raman; Babar, Imran A et al. (2015) MicroRNA silencing for cancer therapy targeted to the tumour microenvironment. Nature 518:107-10
Scanlon, Susan E; Glazer, Peter M (2014) Hypoxic stress facilitates acute activation and chronic downregulation of fanconi anemia proteins. Mol Cancer Res 12:1016-28
Colis, Laureen C; Woo, Christina M; Hegan, Denise C et al. (2014) The cytotoxicity of (-)-lomaiviticin A arises from induction of double-strand breaks in DNA. Nat Chem 6:504-10
Lu, Yuhong; Wajapeyee, Narendra; Turker, Mitchell S et al. (2014) Silencing of the DNA mismatch repair gene MLH1 induced by hypoxic stress in a pathway dependent on the histone demethylase LSD1. Cell Rep 8:501-13
Babar, Imran A; Czochor, Jennifer; Steinmetz, Allison et al. (2011) Inhibition of hypoxia-induced miR-155 radiosensitizes hypoxic lung cancer cells. Cancer Biol Ther 12:908-14
Lu, Yuhong; Chu, Adrian; Turker, Mitchell S et al. (2011) Hypoxia-induced epigenetic regulation and silencing of the BRCA1 promoter. Mol Cell Biol 31:3339-50
Hegan, Denise Campisi; Lu, Yuhong; Stachelek, Gregory C et al. (2010) Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130. Proc Natl Acad Sci U S A 107:2201-6
Stachelek, Gregory C; Dalal, Shibani; Donigan, Katherine A et al. (2010) Potentiation of temozolomide cytotoxicity by inhibition of DNA polymerase beta is accentuated by BRCA2 mutation. Cancer Res 70:409-17
Crosby, Meredith E; Devlin, Cecilia M; Glazer, Peter M et al. (2009) Emerging roles of microRNAs in the molecular responses to hypoxia. Curr Pharm Des 15:3861-6
Crosby, Meredith E; Kulshreshtha, Ritu; Ivan, Mircea et al. (2009) MicroRNA regulation of DNA repair gene expression in hypoxic stress. Cancer Res 69:1221-9

Showing the most recent 10 out of 13 publications