DNA damage response is hijacked by human papillomaviruses to complete their life cycle

Abstract

The DNA damage response (DDR) is activated when DNA is altered by intrinsic or extrinsic agents. This pathway is a complex signaling network and plays important roles in genome stability, tumor transformation, and cell cycle regulation. Human papillomaviruses (HPVs) are the main etiological agents of cervical cancer. Cervical cancer ranks as the fourth most common cancer among women and the second most frequent cause of cancer-related death worldwide. Over 200 types of HPVs have been identified and about one third of these infect the genital tract. The HPV life cycle is associated with epithelial differentiation. Recent studies have shown that HPVs deregulate the DDR to achieve a productive life cycle. In this review, I summarize current findings about how HPVs mediate the ataxia-telangiectasia mutated kinase (ATM) and the ATM-and RAD3-related kinase (ATR) DDRs, and focus on the roles that ATM and ATR signalings play in HPV viral replication. In addition, I demonstrate that the signal transducer and activator of transcription-5 (STAT)-5, an important immune regulator, can promote ATM and ATR activations through different mechanisms. These findings may provide novel opportunities for development of new therapeutic targets for HPV-related cancers.

Keywords: ATM/CHK2; ATR/CHK1; Amplification; DNA damage; Differentiation; Papillomavirus; STAT-5.

Fig. 1

Signaling pathways of ATM and ATR The DNA damage response is activated by ATM, ATR, and DNA-PKcs. All three play central roles in DDR. The ATM-CHK2 and ATR-CHK1 signaling pathways activate the HRR. The ATM and ATR pathways can be activated respectively by DSBs and SSBs. ATM activation can be regulated by Tip60, MRN complex, ATR, and PP2A as well as Wip1. The activated ATM can further trigger the activation of CHK2, SMC-1, FANCD2, BRCA1, as well as H2AX. In addition, the activated CHK2 can phosphorylate Cdc25A and p53. The ATR pathway can be activated by ATRIP, TopBP1, claspin, and 9-1-1 complex. The activation of ATR leads to phosphorylation of various downstream targets such as CHK1, SMC-1, ATM, and p21. Furthermore, CHK1 can facilitate phosphorylation of Wee1, RAD51, Cdc25A, p65, and Rb

Fig. 2

Life cycle of human papillomaviruses HPVs infect basal layer keratinocytes when the basal layer of stratified epithelia is exposed to the virus. On the left, a normal uninfected epithelium is shown for the regular differentiation. On the right, the HPV-infected epithelium is shown with the progress of HPV viral proteins expression. After persisting infection, HPVs replicate with cellular chromosomes in basal cells. Upon the differentiation, more viral genes are observed in differentiated cells. The late gene expression and viral replication are activated, followed by virion assembly and release of newly synthesized virions from the top layers of epithelium

Fig. 3

STAT-5-dependent activation of ATM and ATR pathways, required for HPV genome amplification High-risk HPV activates STAT-5 to mediate TopBP1 transcriptionally to promote ATR pathway. Meanwhile, STAT-5 does not directly regulate Tip60; instead, it partially work through PPARg to manipulate Tip60 activation which consequently facilitates ATM activation. HPV E7 oncogene is responsible for STAT-5 activation as well as interaction with other factors such as Rb, ATM, NBS1, HDAC, and p21. E6 gene may collaborate with other viral proteins to act on Tip60 in addition to its role in p53 degradation. E2 is capable of interacting with TopBP1 to mediate HPV initial replication