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Review
. 2023 Dec:16:200272.
doi: 10.1016/j.tvr.2023.200272. Epub 2023 Oct 31.

Interplay between the DNA damage response and the life cycle of DNA tumor viruses

Caleb J Studstill  1 , Michelle Mac  2 , Cary A Moody  3
Affiliations
Review

Interplay between the DNA damage response and the life cycle of DNA tumor viruses

Caleb J Studstill et al. Tumour Virus Res. 2023 Dec.

Abstract

Approximately 20 % of human cancers are associated with virus infection. DNA tumor viruses can induce tumor formation in host cells by disrupting the cell's DNA replication and repair mechanisms. Specifically, these viruses interfere with the host cell's DNA damage response (DDR), which is a complex network of signaling pathways that is essential for maintaining the integrity of the genome. DNA tumor viruses can disrupt these pathways by expressing oncoproteins that mimic or inhibit various DDR components, thereby promoting genomic instability and tumorigenesis. Recent studies have highlighted the molecular mechanisms by which DNA tumor viruses interact with DDR components, as well as the ways in which these interactions contribute to viral replication and tumorigenesis. Understanding the interplay between DNA tumor viruses and the DDR pathway is critical for developing effective strategies to prevent and treat virally associated cancers. In this review, we discuss the current state of knowledge regarding the mechanisms by which human papillomavirus (HPV), merkel cell polyomavirus (MCPyV), Kaposi's sarcoma-associated herpesvirus (KSHV), and Epstein-Barr virus (EBV) interfere with DDR pathways to facilitate their respective life cycles, and the consequences of such interference on genomic stability and cancer development.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Overview of the cellular DNA damage response. ATM and DNA-PKcs are activated in response to double-strand DNA breaks (DSB). The MRN complex is a DSB sensor and recruits ATM to promote its autophosphorylation and activation. Tip60-mediated acetylation of ATM is required for its full activation. ATM can facilitate repair through HR or NHEJ by initiating a chromatin-based signaling cascade through phosphorylation of H2AX (γH2AX), resulting in the recruitment of the RNF8 and RNF168 ubiquitin ligases to sites of DNA damage. RNF168 ubiquitinates H2A on lys15 to recruit 53BP1, which promotes NHEJ repair, or the BARD1-BRCA1 complex to promote HR repair (not shown). DNA-PKcs is recruited to DSBs by the Ku70/Ku86 complex, which promotes DNA-PKcs autophosphorylation and activation, resulting in repair through NHEJ. ATR is activated in response to ssDNA that forms upon replication fork stalling or resection of DSBs. ATR is recruited to RPA-coated ssDNA by ATRIP. ATR is fully activated by TopBP1, which is recruited to ssDNA by the 9-1-1 complex, or by ETAA1, which is recruited to RPA-coated ssDNA at stalled replication forks. Signaling through DNA damage kinases result in the activation of cell cycle checkpoints to allow time for DNA to be repaired or for cells to undergo apoptosis or senescence if the damage is too severe. Ac = acetylation. P = phosphorylation. Additional details in text. Created using BioRender.com.
Fig. 2
Fig. 2
Interplay between HPV, MCPyV and the DNA damage response. HPV and MCPyV proteins activate components of the ATM and ATR pathways, while HPV E7 blocks DNA-PK activation. HPV episomes are maintained at a low copy number in the undifferentiated, basal cells of the stratified epithelium in a manner that is dependent on ATR activity. In contrast ATM activity is only required for productive replication, which is triggered by epithelial differentiation. Downstream ATM effectors, including RNF168 and factors involved in HR repair (e.g., MRN complex, Rad51, BRCA1) localize to sites of viral replication and are also specifically required for productive replication, indicating that viral genome amplification in differentiating cells occurs in a recombination-dependent manner. E7 interacts pATM, Nbs1 and RNF168, though the impact of these interactions on viral replication is unclear. The E7-RNF168 interaction may provide a pool of RNF168 for recruitment to viral replication foci at the expense of cellular DSB repair, which may contribute to genomic instability in infected cells. Additionally, E7 induces persistent cellular replication stress and activation of the ATR DDR due to unscheduled entry into S-phase. Viral replication in undifferentiated and differentiated cells also results in replication stress that recruits ATR pathway components to viral replication foci. HPV hijacks the ATR replication stress response to increase RRM2 levels and provide dNTPs for viral replication. HPV bypasses oncogene-induced senescence (OIS) associated with DDR signaling through the actions of E7, further fueling genomic instability. MCPyV also requires ATM and ATR activity for replication, though how ATM/ATR signaling contributes to viral replication is currently unclear. ATM and ATR DDR factors localize to sites of viral replication in a manner dependent on LT and the viral origin, including ATM, ATR, γH2AX, Nbs1, pChk2, and pChk1. Full-length LT induces DNA damage and cell cycle arrest in an ATM-p53-dependent manner, which may limit progression to cancer. This may explain why mature merkel cell carcinomas (MCC) express a truncated LT that lacks the C-terminal helicase domain and is impaired for DDR activation and cell cycle arrest. Additional details in text. Created using BioRender.com.
Fig. 3
Fig. 3
Interplay between KSHV, EBV and the DNA damage response. The latent and lytic phases of the KSHV and EBV life cycle each involve commandeering DDR pathways for viral replication as well as disrupting the repair of cellular DSBs, which contributes to genomic instability. KSHV establishes latency in endothelial cells as well as B-cells. EBV primarily establishes latency in memory B-cells but can also establish latency in epithelial cells. De novo KSHV infection of B-cells and endothelial cells induces ATM activation, which is required for the establishment of latency. LANA interacts with γH2AX, which is needed for LANA-mediated persistence of KSHV episomes. Additionally, LANA bypasses cell cycle arrest and apoptosis associated with the DDR by interacting with the ATM effector Chk2 and by blocking the function of p53, respectively. De novo EBV infection of primary B-cells also results in DNA damage and ATM activation due to hyperproliferation driven by the latent proteins EBNA-2A and -2B. ATM activity is ultimately blocked by the latent protein EBNA-3C, allowing for B-cell immortalization and lymphoblastoid cell line (LCL) outgrowth. In contrast, ATR activity is required for B-cell immortalization upon de novo EBV infection. ATM activity is required for both KSHV and EBV lytic replication, and numerous DDR factors localize to sites of viral replication (see text for details). KSHV and EBV lytic proteins contribute to ATM activation, including BGLF4 (EBV) and v-cyclin (KSHV) v-cyclin. While DNA-PK serves as a restriction factor for latent and lytic replication of KSHV and EBV, both viruses encoded proteins that block DNA-PK activation. Several KSHV and EBV proteins induce DNA damage and modulate DNA repair to cause genomic instability. EBNA1 induces the generation of reactive oxygen species (ROS) that cause oxidative DNA damage. Additionally, EBNA1 directly causes cellular DSBs by binding to DNA. KSHV LANA (latent) and EBV BKRF4 (lytic) prevent RNF168 recruitment to cellular DSBs, disrupting NHEJ and possibly HR repair. Additionally, EBV BZLF1 (lytic) disrupts cellular DSB repair by blocking the MDC1-RNF8 interaction at damaged DNA. KSHV ORF57 (lytic) causes genomic instability by inducing DSBs through the formation of R-loops. EBV and KSHV proteins also induce replication stress and DSBs that activate ATM, resulting in OIS. However, both viruses can bypass OIS through the actions of viral proteins, including LMP1 and EBNA-3C for EBV, and vFLIP for KSHV. KSHV (e.g., vIRF1) and EBV (e.g., LMP1, EBNA-3C) proteins also attenuate DDR pathway activation, further contributing to the disruption of cellular DSB repair and genomic instability. Created using BioRender.com.
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