Modulation of the DNA damage response during the life cycle of human papillomaviruses

Abstract

Human papillomavirus (HPV) is the most common sexually transmitted viral infection. Infection with certain types of HPV pose a major public health risk as these types are associated with multiple human cancers, including cervical cancer, other anogenital malignancies and an increasing number of head and neck cancers. The HPV life cycle is closely tied to host cell differentiation with late viral events such as structural gene expression and viral genome amplification taking place in the upper layers of the stratified epithelium. The DNA damage response (DDR) is an elaborate signaling network of proteins that regulate the fidelity of replication by detecting, signaling and repairing DNA lesions. ATM and ATR are two kinases that are major regulators of DNA damage detection and repair. A multitude of studies indicate that activation of the ATM (Ataxia telangiectasia mutated) and ATR (Ataxia telangiectasia and Rad3-related) pathways are critical for HPV to productively replicate. This review outlines how HPV interfaces with the ATM- and ATR-dependent DNA damage responses throughout the viral life cycle to create an environment supportive of viral replication and how activation of these pathways could impact genomic stability.

Topoisomerase 2β-dependent nuclear DNA damage shapes extracellular growth factor responses through AKT phosphorylation dynamics to control virus latency

“…This potentially provides a mechanism to integrate nuclear DNA damage responses with cytoplasmic signaling to control inflammatory responses in a variety of diseases (Crowl et al, 2017;Gao et al, 2015;Li and Chen, 2018;Sliter et al, 2018). It might further expose a strategy used by a variety of nuclear DNA viruses that subvert DNA damage response to support their long-term persistence (Anacker and Moody, 2017;Bencherit et al, 2017;Mariggiò et al, 2017;Piekna-Przybylska et al, 2017).…”

Human papillomavirus 16 E6 and E7 synergistically repress innate immune gene transcription

“…HPV16 must circumvent this, as it would prevent amplification of the viral genome. Therefore, E6 and E7 manipulate constituents of the DDR to allow cell cycle progression in the presence of an active DDR (this has been previously demonstrated (17, 18, 35, 36)), thus preventing cell cycle arrest. Simultaneously, the actions of E6 and E7 repress innate immune response genes and this not only promotes the viral life cycle via immune evasion, but also abrogates the growth inhibitory activity of innate immune signaling.…”

“…It is well established that HPV16 activates the DNA damage response (DDR) in keratinocytes, and that individual over-expression of E6 or E7 can also activate the DDR (17, 18, 20–22, 24, 35, 36). In addition, the E1 protein has also been shown to activate the DDR (23, 25–27).…”

“…In these studies, E6 and E7 have been over expressed from heterologous promoters. HPV16 infected cells also have an active DNA damage response (DDR) turned on at all times; E6, E7 and E1 have all been shown to activate this pathway (17–27). This provides another challenge the virus must overcome, as activation of the DDR stimulates the innate immune response (28).…”

Fighting Cancer with Mathematics and Viruses

“…by promoter elements and pre-mRNA processing. This enables restriction to certain cell types and adaption to changes in the phenotype of the host cell, such as the differentiation of HPV-infected epithelia that is necessary for the virus to complete its life cycle (reviewed in [57][58][59]). The presence of immediate early, early and late genes in herpes viruses [60] relates to different phases of infection and ensures efficient replication before cell lysis.…”