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

PLoS Pathogens
Sujita Khanal, Denise A Galloway

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,...Continue Reading

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Citations

Jan 14, 2021·Proceedings of the National Academy of Sciences of the United States of America·Haibin LiuZhi-Ming Zheng
Dec 31, 2020·Cancers·Sebastian O WendelNicholas A Wallace
Oct 24, 2020·Proceedings of the National Academy of Sciences of the United States of America·Ahmed DiabBruce E Clurman
Nov 21, 2019·Trends in Microbiology·Nicholas A Wallace

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Methods Mentioned

BETA
deubiquitination
de-ubiquitination
transfection
flow cytometry
circumcisions
protein assay
electrophoresis
gene

Software Mentioned

GraphPad Prism
NIH
OpenComet Plugin
TissueFAXS
Deltavision SoftWoRx
FlowJo
Image Lab
ImageJ

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