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
Sulkowski, Parker L; Sundaram, Ranjini K; Oeck, Sebastian et al. (2018) Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair. Nat Genet 50:1086-1092
Kim, Hoon; Lin, Qun; Glazer, Peter M et al. (2018) The hypoxic tumor microenvironment in vivo selects the cancer stem cell fate of breast cancer cells. Breast Cancer Res 20:16
Sulkowski, Parker L; Scanlon, Susan E; Oeck, Sebastian et al. (2018) PTEN Regulates Nonhomologous End Joining By Epigenetic Induction of NHEJ1/XLF. Mol Cancer Res 16:1241-1254
Lu, Yuhong; Liu, Yanfeng; Oeck, Sebastian et al. (2018) Hypoxia Promotes Resistance to EGFR Inhibition in NSCLC Cells via the Histone Demethylases, LSD1 and PLU-1. Mol Cancer Res 16:1458-1469
Scanlon, Susan E; Hegan, Denise C; Sulkowski, Parker L et al. (2018) Suppression of homology-dependent DNA double-strand break repair induces PARP inhibitor sensitivity in VHL-deficient human renal cell carcinoma. Oncotarget 9:4647-4660
Scanlon, Susan E; Scanlon, Christine D; Hegan, Denise C et al. (2017) Nickel induces transcriptional down-regulation of DNA repair pathways in tumorigenic and non-tumorigenic lung cells. Carcinogenesis 38:627-637
Gupta, Anisha; Quijano, Elias; Liu, Yanfeng et al. (2017) Anti-tumor Activity of miniPEG-?-Modified PNAs to Inhibit MicroRNA-210 for Cancer Therapy. Mol Ther Nucleic Acids 9:111-119
Sulkowski, Parker L; Corso, Christopher D; Robinson, Nathaniel D et al. (2017) 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci Transl Med 9:
Yu, Chang; Zelterman, Daniel (2017) A parametric model to estimate the proportion from true null using a distribution for p-values. Comput Stat Data Anal 114:105-118
Czochor, Jennifer R; Sulkowski, Parker; Glazer, Peter M (2016) miR-155 Overexpression Promotes Genomic Instability by Reducing High-fidelity Polymerase Delta Expression and Activating Error-Prone DSB Repair. Mol Cancer Res 14:363-73

Showing the most recent 10 out of 29 publications