Rewiring of epigenetic DNA damage response pathways in HPV-induced cancer

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Project summary/abstract Infection with human papilloma virus (HPV) causes endemic occurrence of cervical, head and neck and anal cancers. Radiotherapy is the cornerstone treatment for these tumors. However, clinical outcomes in patients with locally advanced disease remain poor due to high recurrence rates. Thus, there is a critical need to improve the efficacy of radiation in these tumors. Epigenetic signaling pathways play a crucial role in DNA damage response providing suitable clinical targets for improving the efficacy of radiotherapy. We demonstrate that expression of the HPV proteins E6 and E7 alters epigenetic signaling in cancer cells. We hypothesize that these epigenomic alterations cause tumor dependence on alternative epigenetic pathways to cope with DNA damage. Using a CRISPR/Cas9 screen we discovered that HPV-positive cancer cells selectively depend on the chromatin modifier NSL1 and the E3 ubiquitin ligase RNF168 to survive radiation. The goal of this proposal is to determine the mechanisms of DNA damage response (DDR) regulated by these pathways in the setting of HPV-induced epigenetic changes. Our work will establish a novel concept of tumor-targeted therapy by harnessing HPV- induced epigenomic alterations to allow specific targeting of cancer cells while sparing healthy tissues. The work proposed here will be conducted under the mentorship of Dr. Dennis Hallahan, a leader clinical and experimental radiation oncology. The candidate is an MD/PhD with training in clinical radiation oncology who seeks further training in basic research. His long-term goal is to establish an independent research laboratory studying the role of epigenetics in DDR. It is anticipated that the project will result in impactful contributions to the fields of DDR and Radiation Oncology and prepare the candidate for a career as an independent investigator.