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Review
. 2018 Sep 29;5(1):141-164.
doi: 10.1146/annurev-virology-092917-043534. Epub 2018 Jul 11.

Virus DNA Replication and the Host DNA Damage Response

Matthew D Weitzman  1   2 , Amélie Fradet-Turcotte  3   4
Affiliations
Review

Virus DNA Replication and the Host DNA Damage Response

Matthew D Weitzman et al. Annu Rev Virol. .

Abstract

Viral DNA genomes have limited coding capacity and therefore harness cellular factors to facilitate replication of their genomes and generate progeny virions. Studies of viruses and how they interact with cellular processes have historically provided seminal insights into basic biology and disease mechanisms. The replicative life cycles of many DNA viruses have been shown to engage components of the host DNA damage and repair machinery. Viruses have evolved numerous strategies to navigate the cellular DNA damage response. By hijacking and manipulating cellular replication and repair processes, DNA viruses can selectively harness or abrogate distinct components of the cellular machinery to complete their life cycles. Here, we highlight consequences for viral replication and host genome integrity during the dynamic interactions between virus and host.

Keywords: DNA damage response; chromatin state; viral genome; virus replication; virus replication compartments.

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Figures

Figure 1
Figure 1
DNA damage responses to double-strand breaks (DSBs) and single-stranded DNA (ssDNA). (Middle panel) Sensing DNA damage. DNA DSBs are sensed by the MRN complex and signaled by activation of ATM. Accumulation of ssDNA at stalled or stressed replication forks triggers activation of ATR. Solid and dashed arrows indicate direct and indirect interactions, respectively. Proteins regulated in a cell cycle-dependent manner are color coded by the stage of the cell cycle at which they are activated. (Lower panel) DNA damage signaling is induced following activation of transducer kinases. Upon DSBs, phosphorylation of H2AX (γ-H2AX) initiates recruitment of MDC1, RNF8, and RNF168 in a hierarchal manner. In G1, accumulation of 53BP1 and RIF1 at the break promotes repair by nonhomologous end joining (NHEJ). In S-G2, homologous recombination repair (HRR) is promoted by the complex BRCA1-CtIP. At stalled/stressed forks, accumulation ofRPA-coated ssDNA induces recruitment ofATRIP, the RAD17-RFC2–5 clamp loader and RAD9-RAD1-HUS1 (9–1–1) checkpoint clamps, and TOPBP1 at the fork. Full activation of ATR is achieved through its interaction with ATRIP and TOPBP1. (Upper panel) In order to prevent replication of damaged DNA, activation ofDNA damage signaling is coupled with activation of cell cycle checkpoints that stop cell cycle progression. Both ATM and ATR activate checkpoint kinases (CHK2 and CHK1, respectively) in a phosphorylation-dependent manner. These kinases induce G1–S checkpoint arrest by activating the tumor suppressor p53. The intra-S phase or G2–M checkpoints are activated when the phosphatases cell division cycle 25 (CDC25) and WEE1 are inhibited by the checkpoint kinases.
Figure 2
Figure 2
DNA repair pathways—a toolkit for viral replication. (a) Classical nonhomologous end joining occurs through limited DNA end processing and religation. This repair pathway is thought to mediate viral genome integration into host genomes and can also affect concatemer formation. (b) Homologous recombination repair is triggered when DNA ends are extensively resected and coated with RPA. Subsequently, the recruitment of RAD51 by the action of BRCA1, BRCA2, and PALB2 leads to homology search and the formation of a displacement loop (D loop) upon invasion of the homologous template. D loops are resolved by synthesis-dependent strand annealing (SDSA) or by processing of a Holliday junction (HJ). The latter processes can be achieved through the actions of endonucleases (resolution) or by combining the activities of a helicase and a topoisomerase (dissolution). Many viruses have been reported to rely on homologous recombination repair to replicate. For example, the endonuclease activity ofMREll as well as the resolvase processes intermediates created upon replication of circular genomes and concatemers. (c) Stalled or stressed replication forks can either restart or collapse. Stabilization of the fork by ATR enables the fork to bypass a DNA lesion and restart (4). Alternatively, the fork can be processed by nucleases (MRE11, DNA2,WRN, EXO1, CtIP) and translocases (ZRANB3, SMARCAL1). BRCA1, BRCA2, RAD51, and FANCD2 protect forks from extended resection in this process. This pathway is particularly important to support high levels of viral replication where viral helicases may be more prone to collapse. Virus abbreviations: EBV, Epstein-Barr virus; HPV, human papillomavirus; HSV-1, herpes simplex virus type 1; KSHV, Kaposi’s sarcoma-associated herpesvirus; SV40, simian virus 40; VAVC, vaccinia virus.
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