High-risk human papillomavirus oncogenes disrupt the Fanconi anemia DNA repair pathway by impairing localization and de-ubiquitination of FancD2.

Publication Type:

Journal Article

Source:

PLoS pathogens, Volume 15, Issue 2, p.e1007442 (2019)

Keywords:

Alphapapillomavirus, Cisplatin, DNA Damage, DNA repair, Fanconi Anemia Complementation Group D2 Protein, Fanconi Anemia Complementation Group N Protein, Fanconi Anemia Complementation Group Proteins, Flow Cytometry Core Facility, GENOMIC INSTABILITY, HEK293 Cells, Humans, Oncogene Proteins, Viral, Oncogenes, Papillomavirus E7 Proteins, Primary Cell Culture, Repressor Proteins, Scientific Imaging Core Facility, Signal Transduction, UBIQUITINATION

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.