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. 2011 Jul;6(7):813-830.
doi: 10.2217/fvl.11.55.

At a crossroads: human DNA tumor viruses and the host DNA damage response

Pavel A Nikitin  1 , Micah A Luftig
Affiliations

At a crossroads: human DNA tumor viruses and the host DNA damage response

Pavel A Nikitin et al. Future Virol. 2011 Jul.

Abstract

Human DNA tumor viruses induce host cell proliferation in order to establish the necessary cellular milieu to replicate viral DNA. The consequence of such viral-programmed induction of proliferation coupled with the introduction of foreign replicating DNA structures makes these viruses particularly sensitive to the host DNA damage response machinery. In fact, sensors of DNA damage are often activated and modulated by DNA tumor viruses in both latent and lytic infection. This article focuses on the role of the DNA damage response during the life cycle of human DNA tumor viruses, with a particular emphasis on recent advances in our understanding of the role of the DNA damage response in EBV, Kaposi's sarcoma-associated herpesvirus and human papillomavirus infection.

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Figures

Figure 1
Figure 1. DNA damage response to single-stranded and double-stranded breaks
(A) ssDNA is coated by RPA and subsequently recognized by an ATR–ATRIP complex, while the RAD9–RAD1–HUS1 (9–1–1) complex binds to the 5′ overhang near the exposed ssDNA. The 9–1–1 complex brings the adaptor TOPBP1 that activates ATR in the presence of ATRIP and leads to ATR-mediated phosphorylation of downstream targets including Chk1 and p53. (B) DNA double-stranded breaks are detected by the Mre11–Rad50–Nbs1 complex, which promotes monomerization and autophosphorylation of the ATM kinase at Ser1981. Activated ATM initiates a downstream cascade of events, including phosphorylation and activation of its downstream effector Chk2 kinase at Thr-68, p53 at Ser-15, H2AX tail at Ser-139 (γH2AX) and Nbs1 at Ser343, as well as the phosphorylation of more than 180 targets. The phosphorylation of H2AX serves as a scaffold for the recruitment of MDC1 (not shown) and 53BP1 (among other proteins) at the site of the dsDNA breaks, enabling signal amplification and propagation. ATM: Ataxia-telangiectasia mutated kinase; ATR: Ataxia-telangiectasia and RAD3-related kinase; ATRIP: Ataxia-telangiectasia and RAD3-related kinase-interacting protein; RPA: Replication protein A; TOPBP: Topoisomerase binding protein.
Figure 2
Figure 2. EBV infection activates the host DNA damage response
(A) EBV infection of human primary B lymphocytes in vitro initiates EBNA2 and EBNA-LP-mediated c-Myc expression leading to cellular hyperproliferation and activation of an ATM/Chk2-dependent DNA damage response (DDR). Importantly, DDR foci are not co-localized with viral episomes. As infected cells proliferate five to six times, expression of the essential viral oncoproteins EBNA3C and LMP1 (among others) attenuates cellular proliferation leading to downregulation of the host DDR and growth transformation of infected cells into lymphoblastoid cell lines. (B) Transfection of individual viral latency proteins in BL-derived cells modifies DDR signaling. LMP1 expression represses ATM expression; EBNA3C abolishes the mitotic spindle checkpoint through downregulation of BubR1 and leads to EBNA3C:Chk2 complex formation; whereas EBNA1 expression, through induction of ROS, activates ATM and leads to phosphorylation of H2AX. (C) Lytic EBV viral DNA replication generates double-stranded breaks (shown as sparks) that activate ATM downstream signaling. The EBV major tegument protein BPLF1 induces cellular DNA hyper-replication through stabilization of the licensing factor Cdt1. The consequent unchecked S-phase activates an ATR- (not shown) and ATM-dependent DDR. However, viral lytic protein Zta, or BZLF1, binds to 53BP1, promoting the lytic cycle and also inhibits p53 through multiple mechanisms. ATM: Ataxia-telangiectasia mutated kinase; BL: Burkitt’s lymphoma; EBNA: EBV nuclear antigen; LMP: Latent membrane protein; ROS: Reactive oxygen species.
Figure 3
Figure 3. Kaposi’s sarcoma virus targets the host DNA damage response
(A) KSHV latently infected endothelial cells within early KS lesions display an activated ATM/Chk2-mediated DDR, likely mediated through v-cyclin-driven cellular proliferation, centrosome duplication and LANA targeting of growth suppressive pathways. Later, KSHV latent infection is characterized by attenuated ATM/Chk2 signaling, which may be a result of selection of mutated DDR pathway components, disruption of cellular checkpoints, and LANA binding to p53. (B) KSHV lytic replication likely activates ATM, similarly to Figure 2C. To promote KSHV replication, the viral lytic product vIRF1 interacts with ATM and manipulates p53 function. ATM: Ataxia-telangiectasia mutated kinase; DDR: DNA damage response; KS: Kaposi’s sarcoma; KSHV: Kaposi’s sarcoma-associated herpesvirus; LANA: Latency-associated nuclear antigen.
Figure 4
Figure 4. Human papillomavirus manipulates the host ataxia-telangiectasia mutated signaling
(A) Basal epithelial cell infection by HPV (left) leads to expression of viral E1, E2, E6 and E7 proteins, which activate ATM/Chk2 and ataxia-telangiectasia and RAD3-related kinase/Chk1 (not shown) signaling (middle). Episome DNA replication through a theta intermediate likely maintains the HPV genome in infected undifferentiated keratinocytes. In Ca2+-differentiated keratinocytes (right), where viral episome amplification occurs through a possible rolling circle mechanism, Nbs1 is also phosphorylated and ATM and Chk2 are important for viral DNA replication. The E7 protein binds to activated ATM (or activates ATM through binding) and manipulates ATM signaling (B). (B) Putative mechanism of caspase-cleaved E1-dependent genome amplification in differentiated cells. The HPV E7:pATM complex (or HPV DNA) leads to modest activation (dashed arrow) of caspases 3 and/or 7, not inducing apoptosis, but resulting in E1 cleavage, which is required for HPV genome amplification. ATM: Ataxia-telangiectasia mutated kinase; HPV: Human papillomavirus.
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