Human papillomavirus (HPV) infection leads to a variety of benign lesions and malignant tumors such as cervical cancer and head and neck squamous cell carcinoma. Several HPV vaccines have been developed that can help to prevent cervical carcinoma, but these vaccines are only effective in individuals with no prior HPV infection. Thus, it is still important to understand the HPV life cycle and in particular the association of HPV with human pathogenesis. HPV production requires activation of the DNA damage response (DDR), which is a complex signaling network composed of multiple sensors, mediators, transducers, and effectors that safeguard cellular DNAs to maintain the host genome integrity. In this review, we focus on the roles of the ataxia telangiectasia mutant and Rad3-related (ATR) DNA damage response in HPV DNA replication. HPV can induce ATR expression and activate the ATR pathway. Inhibition of the ATR pathway results in suppression of HPV genome maintenance and amplification. The mechanisms underlying this could be through various molecular pathways such as checkpoint signaling and transcriptional regulation. In light of these findings, other downstream mechanisms of the ATR pathway need to be further investigated for better understanding HPV pathogenesis and developing novel ATR DDR-related inhibitors against HPV infection.
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