Luo Ying, Hong Shiyuan
Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China.
Pathogens. 2020 Jun 23;9(6):506. doi: 10.3390/pathogens9060506.
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.
人乳头瘤病毒（HPV）感染会导致多种良性病变和恶性肿瘤，如宫颈癌和头颈部鳞状细胞癌。已经研发出几种HPV疫苗，它们有助于预防宫颈癌，但这些疫苗仅对未曾感染过HPV的个体有效。因此，了解HPV的生命周期，尤其是HPV与人类发病机制的关联仍然很重要。HPV的产生需要激活DNA损伤反应（DDR），这是一个由多个传感器、介质、转导器和效应器组成的复杂信号网络，可保护细胞DNA以维持宿主基因组的完整性。在这篇综述中，我们重点关注共济失调毛细血管扩张症突变体和Rad3相关蛋白（ATR）DNA损伤反应在HPV DNA复制中的作用。HPV可诱导ATR表达并激活ATR途径。抑制ATR途径会导致HPV基因组维持和扩增受到抑制。其潜在机制可能是通过各种分子途径，如检查点信号传导和转录调控。鉴于这些发现，需要进一步研究ATR途径的其他下游机制，以更好地理解HPV发病机制，并开发针对HPV感染的新型ATR DDR相关抑制剂。
