Abstract
Persistent expression of high-risk HPV oncogenes is necessary for the development of anogenital and oropharyngeal cancers. Here, we show that E6/E7 expressing cells are hypersensitive to DNA crosslinking agent cisplatin and have defects in repairing DNA interstrand crosslinks (ICL). Importantly, we elucidate how E6/E7 attenuate the Fanconi anemia (FA) DNA crosslink repair pathway. Though E6/E7 activated the pathway by increasing FancD2 monoubiquitination and foci formation, they inhibited the completion of the repair by multiple mechanisms. E6/E7 impaired FancD2 colocalization with double-strand breaks (DSB), which subsequently hindered the recruitment of the downstream protein Rad51 to DSB in E6 cells. Further, E6 expression caused delayed FancD2 de-ubiquitination, an important process for effective ICL repair. Delayed FancD2 de-ubiquitination was associated with the increased chromatin retention of FancD2 hindering USP1 de-ubiquitinating activity, and persistently activated ATR/CHK-1/pS565 FancI signaling. E6 mediated p53 degradation did not hamper the cell cycle specific process of FancD2 modifications but abrogated repair by disrupting FancD2 de-ubiquitination. Further, E6 reduced the expression and foci formation of Palb2, which is a repair protein downstream of FancD2. These findings uncover unique mechanisms by which HPV oncogenes contribute to genomic instability and the response to cisplatin therapies.
Highlights
High-risk human papillomavirus (HR-HPV) E6/E7 oncoproteins are essential for the development of malignancies of the anogenital tract and oropharynx, with HPV16 being the predominant type [1]
E6/E7 causes accumulation of FancD2, a central component of the Fanconi anemia (FA) pathway, at the sites away from DNA damage. This results in reduced recruitment of Rad51, another repair protein involved in the pathway
To further elucidate the mechanisms by which HPV oncogenes impair DNA damage repair (DDR), the present study focuses on the impact of HPV16 oncogenes on the Fanconi anemia-BRCA (FA or FA-BRCA) pathway
Summary
High-risk human papillomavirus (HR-HPV) E6/E7 oncoproteins are essential for the development of malignancies of the anogenital tract and oropharynx, with HPV16 being the predominant type [1]. Cervical and oropharyngeal cancers are the most common HPV-associated malignancies among females and males, respectively [2]. Persistent HPV infection destabilizes the cellular genome which can lead to cancer. Genomic instability is likely the result of the numerous interactions of HPV oncoproteins with host tumor suppressors and DNA damage repair (DDR) proteins. We demonstrated that high-risk HPV oncogenes attenuate double-strand break (DSB) repair by impairing the homologous recombination pathway [3]. To further elucidate the mechanisms by which HPV oncogenes impair DDR, the present study focuses on the impact of HPV16 oncogenes on the Fanconi anemia-BRCA (FA or FA-BRCA) pathway
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