Widespread use of prophylactic vaccines to prevent infection with high-risk human papillomaviruses (HR- HPVs) has the potential to significantly reduce the burden of anogenital and oropharyngeal cancers. But for many millions of people who are already infected with HPV, or will not be vaccinated, HPV associated cancers remain a serious problem. HPV infection causes DNA damage and the persistent expression of the viral oncoproteins, E6 and E7, not only causes damage but inhibits the repair of DNA damage (DDR). We have shown that the E6 and E7 proteins either singly or in combination affect the DDR signaling cascades by increasing the number and persistence of repair foci including ?H2AX, ATM, ATR, CHK1, CHK2, BRCA1, BRCA2, RPA and RAD51. RPA foci were shown to exist in cells outside of S phase, and RAD51 foci were shown to mislocalize. We will investigate the mechanisms by which E6 and E7 deregulate double strand break (DSB) repair, the most deleterious form of DNA damage. We will also determine the mechanisms by which E6 and E7 disrupt the Fanconi Anemia-BRCA pathway in the repair of interstrand cross links (ICLs) and stalled replication forks, as cisplatin, the most commonly used chemotherapy for HPV associated cancers causes ICLs. Defects in the DDR are observed in most cancers and underlie the principle of using genotoxic chemotherapy. With drugs to target the DDR pathways on the horizon we believe that understanding the defects caused by HR-HPVs in Aims 1 and 2 will improve the therapeutic options for individuals with HPV associated cancers.
Our third aim will be to test the sensitivity in a variety of HR-HPV cells, to DDR inhibitors alone and in combination with chemotherapeutic drugs. Thus the significance of the potential outcomes of this proposal will be an enhanced understanding of the HPV-DDR axis, and harnessing the knowledge to improve therapy for HPV associated cancers.
Individuals who are infected with high-risk human papillomaviruses (HR-HPVs) or who will not be vaccinated are at risk for a host of HPV-associated cancers. We propose to gain a more complete understand of how HPVs impair the response to DNA damage and to exploit those repair deficiencies to generate better therapeutic options for HPV associated cancers.
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