β-HPV 8E6 Attenuates ATM and ATR Signaling in Response to UV Damage.

Jazmine A Snow,Changkun Hu,Vaibhav Murthy,Nicholas A Wallace,Dalton Dacus

doi:10.3390/pathogens8040267

Abstract

Given the high prevalence of cutaneous genus beta human papillomavirus (β-HPV) infections, it is important to understand how they manipulate their host cells. This is particularly true for cellular responses to UV damage, since our skin is continually exposed to UV. The E6 protein from β-genus HPV (β-HPV E6) decreases the abundance of two essential UV-repair kinases (ATM and ATR). Although β-HPV E6 reduces their availability, the impact on downstream signaling events is unclear. We demonstrate that β-HPV E6 decreases ATM and ATR activation. This inhibition extended to XPA, an ATR target necessary for UV repair, lowering both its phosphorylation and accumulation. β-HPV E6 also hindered POLη accumulation and foci formation, critical steps in translesion synthesis. ATM’s phosphorylation of BRCA1 is also attenuated by β-HPV E6. While there was a striking decrease in phosphorylation of direct ATM/ATR targets, events further down the cascade were not reduced. In summary, despite being incomplete, β-HPV 8E6’s hindrance of ATM/ATR has functional consequences.

Highlights

The human papillomavirus (HPV) family is made up of five genera, each containing a large number of individual HPV types [1,2]
We have previously reported that β-HPV 8E6 decreases ATM and ATR abundance [30,31]
We focused our analysis on genes that belonged to two pathways involved in UV repair responses, namely nucleotide excision repair (NER) and translesion synthesis (TLS) as well as a few canonical ATR/ATM targets (BRCA1, CHEK1, CDC25A, and TP53) [47,48,49,50,51]

Summary

Introduction

The human papillomavirus (HPV) family is made up of five genera (alpha, beta, gamma, mu and nu papillomaviruses), each containing a large number of individual HPV types [1,2] The division into these groups is based on differences in the major capsid gene’s sequence [3,4]. Β-HPV infections are thought to act through a “hit and run” mechanism of oncogenesis [16,17] This hypothesis holds that β-HPV infections act synergistically along with UV radiation to promote tumorigenic mutations that cause lasting changes to the cellular environment without being dependent on continued expression of β-HPV’s putative oncogenes (β-HPV E6 and E7) [18]

Methods

Results

Conclusion