Viral manipulation of DNA repair and cell cycle checkpoints

Chaurushiya, Mira S.; Weitzman, Matthew D.

doi:10.1016/j.dnarep.2009.04.016

Cited by 110 publications

(104 citation statements)

References 180 publications

(217 reference statements)

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“…Distinct strategies, including activation of DNA damage response and recruitment of DNA repair proteins to viral replication centers were found to be used by different viruses to manipulate host DNA damage response and viral replication (19,21). As activation of DNA damage response can promote apoptosis, viruses have also evolved ways to tailor the damage signaling by targeting a specific sensor or a repair protein for degradation or mislocalization to suppress the downstream signaling.…”

Section: Discussionmentioning

confidence: 99%

“…Many DNA viruses have evolved mechanisms to override normal checkpoint control and force cells into S phase to ensure an abundant supply of nucleotides and other essential replication factors during their replication cycles (21,81). Evidence provided in this study demonstrated that the same strategy was also exploited by Coronavirus, an RNA virus that exclusively replicates its RNA in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

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Coronavirus Infection Induces DNA Replication Stress Partly through Interaction of Its Nonstructural Protein 13 with the p125 Subunit of DNA Polymerase δ

Huang

Fang

et al. 2011

Journal of Biological Chemistry

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Perturbation of cell cycle regulation is a characteristic feature of infection by many DNA and RNA viruses, including Coronavirus infectious bronchitis virus (IBV). IBV infection was shown to induce cell cycle arrest at both S and G 2 /M phases for the enhancement of viral replication and progeny production. However, the underlying mechanisms are not well explored. In this study we show that activation of cellular DNA damage response is one of the mechanisms exploited by Coronavirus to induce cell cycle arrest. An ATR-dependent cellular DNA damage response was shown to be activated by IBV infection. Suppression of the ATR kinase activity by chemical inhibitors and siRNA-mediated knockdown of ATR reduced the IBV-induced ATR signaling and inhibited the replication of IBV. Furthermore, yeast two-hybrid screens and subsequent biochemical and functional studies demonstrated that interaction between Coronavirus nsp13 and DNA polymerase ␦ induced DNA replication stress in IBV-infected cells. These findings indicate that the ATR signaling activated by IBV replication contributes to the IBV-induced S-phase arrest and is required for efficient IBV replication and progeny production.DNA damage response is a signal transduction pathway that coordinates cell cycle transition, DNA replication, and repair in response to DNA damage or replication stress (1, 2). It is essential for maintenance of genome integrity and cell survival. DNA damage response is primarily mediated by two related protein kinases, the ataxia-telangiectasia mutated (ATM) 2 and ATM/ Rad3-related (ATR). ATM is activated as a result of doublestranded breaks (DSBs) and is recruited to DSBs by Mre11-Rad50-NBS1 complex (3, 4). ATR, on the other hand, is activated by a wide range of DNA damage, including stalled DNA replication forks and the subsequent single-stranded lesion (ssDNA), base adducts, ultraviolet (UV)-induced nucleotide damage, and double-stranded breaks during S phase (1, 5). ATR is recruited to replication factor A (RPA)-coated ssDNA by ATR-interacting protein (ATRIP) (6, 7). When ATM or ATR is recruited to sites of damage, they phosphorylate and activate different substrates, including checkpoint kinase-2 (CHK2) and CHK1, respectively (1,8,9). A large number of overlapping substrates of ATM and ATR that might be involved in DNA damage response has been presented (e.g. H2AX, RPA32, p53, BRCA1) (10, 11). Those signaling modules finally lead to cell cycle arrest to allow for DNA repair or apoptosis in cases of severe DNA damage. In contrast to ATM, ATR prevents replication fork collapse at stalled replication forks and is essential for cell viability (7,(12)(13)(14)(15)(16)(17)(18).Many DNA viruses and retroviruses, including Epstein-Barr virus, herpes simplex virus 1, human Papillomavirus 16, human immunodeficiency virus (HIV), adenovirus, simian virus 40 (SV40), and Polyomavirus, are known to eliminate, circumvent, or exploit various aspects of cellular DNA damage response machinery to maximize their own replication. In RNA virus families, however,...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Coronavirus Infection Induces DNA Replication Stress Partly through Interaction of Its Nonstructural Protein 13 with the p125 Subunit of DNA Polymerase δ

Huang

Fang

et al. 2011

Journal of Biological Chemistry

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“…In addition to recognizing cellular DNA lesions, there is increasing evidence to show that this response is also activated by viral DNA during infection, and that some DNA repair proteins can inhibit viral replication (2).…”

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confidence: 99%

Adenovirus 12 E4orf6 inhibits ATR activation by promoting TOPBP1 degradation

Blackford

Patel

Forrester

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Activation of the cellular DNA damage response is detrimental to adenovirus (Ad) infection. Ad has therefore evolved a number of strategies to inhibit ATM-and ATR-dependent signaling pathways during infection. Recent work suggests that the Ad5 E4orf3 protein prevents ATR activation through its ability to mislocalize the MRN complex. Here we provide evidence to indicate that Ad12 has evolved a different strategy from Ad5 to inhibit ATR. We show that Ad12 utilizes a CUL2/RBX1/elongin C-containing ubiquitin ligase to promote the proteasomal degradation of the ATR activator protein topoisomerase-IIβ-binding protein 1 (TOPBP1). Ad12 also uses this complex to degrade p53 during infection, in contrast to Ad5, which requires a CUL5-based ubiquitin ligase. Although Ad12-mediated degradation of p53 is dependent upon both E1B-55K and E4orf6, Ad12-mediated degradation of TOPBP1 is solely dependent on E4orf6. We propose that Ad12 E4orf6 has two principal activities: to recruit the CUL2-based ubiquitin ligase and to act as substrate receptor for TOPBP1. In support of the idea that Ad12 E4orf6 specifically prevents ATR activation during infection by targeting TOPBP1 for degradation, we demonstrate that Ad12 E4orf6 can inhibit the ATR-dependent phosphorylation of CHK1 in response to replication stress. Taken together, these data provide insights into how Ad modulates ATR signaling pathways during infection.DNA damage | cullin-RING ubiquitin ligases | DNA damage | proteasome

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“…Several virus-encoded products have been associated with transforming and/or oncomodulatory activities [4] , and with the ability to induce chromosome damage, abnormal mitosis and genetic instability when expressed in cell cultures (Table 2) [18,[36][37][38] . Recent findings point to viral proteins interfering with the epigenetic milieu of the infected cells, leading to the transcriptional repression of tumor suppressor genes, and interference with cell cycling control [39] (Table 3).…”

Section: A Mechanism For Tumor Initiation In Viral Persistencementioning

confidence: 99%

How virus persistence can initiate the tumorigenesis process

Avanzi

Alvisi²,

Ripalti³

2013

WJV

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Human oncogenic viruses are defined as necessary but not sufficient to initiate cancer. Experimental evidence suggests that the oncogenic potential of a virus is effective in cells that have already accumulated a number of genetic mutations leading to cell cycle deregulation. Current models for viral driven oncogenesis cannot explain why tumor development in carriers of tumorigenic viruses is a very rare event, occurring decades after virus infection. Considering that viruses are mutagenic agents per se and human oncogenic viruses additionally establish latent and persistent infections, we attempt here to provide a general mechanism of tumor initiation both for RNA and DNA viruses, suggesting viruses could be both necessary and sufficient in triggering human tumorigenesis initiation. Upon reviewing emerging evidence on the ability of viruses to induce DNA damage while subverting the DNA damage response and inducing epigenetic disturbance in the infected cell, we hypothesize a general, albeit inefficient hit and rest mechanism by which viruses may produce a limited reservoir of cells harboring permanent damage that would be initiated when the virus first hits the cell, before latency is established. Cells surviving virus generated damage would consequently become more sensitive to further damage mediated by the otherwise insufficient transforming activity of virus products expressed in latency, or upon episodic reactivations (viral persistence). Cells with a combination of genetic and epigenetic damage leading to a cancerous phenotype would emerge very rarely, as the probability of such an occurrence would be dependent on severity and frequency of consecutive hit and rest cycles due to viral reinfections and reactivations

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Viral manipulation of DNA repair and cell cycle checkpoints

Cited by 110 publications

References 180 publications

Coronavirus Infection Induces DNA Replication Stress Partly through Interaction of Its Nonstructural Protein 13 with the p125 Subunit of DNA Polymerase δ

Coronavirus Infection Induces DNA Replication Stress Partly through Interaction of Its Nonstructural Protein 13 with the p125 Subunit of DNA Polymerase δ

Adenovirus 12 E4orf6 inhibits ATR activation by promoting TOPBP1 degradation

How virus persistence can initiate the tumorigenesis process

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