Using or abusing: viruses and the cellular DNA damage response

doi:10.1016/j.tim.2007.01.003

Trends in Microbiology

Volume 15, Issue 3, March 2007, Pages 119-126

https://doi.org/10.1016/j.tim.2007.01.003 Get rights and content

During infection, viruses attempt to hijack the cell while the host responds with various defense systems. Traditional defenses include the interferon response and apoptosis, but recent work suggests that this antiviral arsenal also includes the cellular DNA damage response machinery. The observation of interactions between viruses and cellular DNA repair proteins has not only uncovered new complexities of the virus–host interaction but is also reinforcing the view that viruses can reveal key regulators of cellular pathways through the proteins they target.

Section snippets

The cellular DNA damage response

Cellular DNA is constantly under assault from both endogenous and exogenous sources. Maintaining an undamaged genome is a continuous challenge; it has been estimated that each cell must repair over 10 000 DNA lesions per day [1]. Cells have elaborate machinery in place to monitor damage and ensure the fidelity of replication 2, 3. Upon sensing damage, cells initiate signaling pathways that result in activation of checkpoints to prevent replication of damaged DNA. The DNA repair proteins

Viruses and the cellular DNA repair machinery

Recent work has suggested that the cellular DNA repair machinery can recognize viral genetic material as ‘damage’ [4]. Attempts to process the viral genome could have detrimental results, so some viruses have developed ways to inhibit or circumvent the host-cell response. For other viruses, the cellular response seems to be beneficial, and viruses have evolved ways to hijack cellular DNA repair proteins to aid their own replication.

Consequences for the cell

Viruses are intracellular parasites, and as such they depend on host cell functions for their replication. Viruses must therefore ensure that the health of the cell is maintained long enough to maximize production of viral progeny.

Consequences for the virus

The fate of the virus depends on the cellular environment it encounters upon infection. Many infection events do not result in productive viral replication and this can partly depend on the DNA damage response environment of the host.

Concluding remarks

The interaction of viruses with the host cell DNA repair machinery is elaborate, and we are just beginning to understand the complexity of the interplay. Figure 2 highlights the cellular DNA repair proteins targeted by the viral factors we have discussed. In general terms, viruses respond to the cellular DNA damage response either by disabling key cellular proteins or activating, recruiting and exploiting host cell factors to aid viral replication. It is likely that virus responses are

Acknowledgements

We apologize to the many groups whose primary research papers could not be cited owing to space constraints. We thank members of the Weitzman laboratory and our many collaborators for helpful discussions and we are grateful to Jamie Simon for assistance with the figures. C.E.L was supported by a Wellcome Trust International Research Fellowship (GR066559). R.A.S. received a scholarship from the ARCS Foundation. Work on viruses and DNA repair in the author's laboratory is supported by grants from

References (80)

C.J. Bakkenist et al.
Initiating cellular stress responses
Cell
(2004)
M.D. Weitzman
Interactions of viruses with the cellular DNA repair machinery
DNA Repair (Amst.)
(2004)
N. Shirata
Activation of ataxia telangiectasia-mutated DNA damage checkpoint signal transduction elicited by herpes simplex virus infection
J. Biol. Chem.
(2005)
A. Kudoh
Epstein-Barr virus lytic replication elicits ATM checkpoint signal transduction while providing an S-phase-like cellular environment
J. Biol. Chem.
(2005)
Y. Shi
Ataxia-telangiectasia-mutated (ATM) is a T-antigen kinase that controls SV40 viral replication in vivo
J. Biol. Chem.
(2005)
T. Daikoku
Postreplicative mismatch repair factors are recruited to Epstein-Barr virus replication compartments
J. Biol. Chem.
(2006)
M. Roshal
Activation of the ATR-mediated DNA damage response by the HIV-1 viral protein R
J. Biol. Chem.
(2003)
G. Nunnari
Inhibition of HIV-1 replication by caffeine and caffeine-related methylxanthines
Virology
(2005)
J. Boyer
Adenovirus E4 34k and E4 11k inhibit double strand break repair and are physically associated with the cellular DNA-dependent protein kinase
Virology
(1999)
W. Boner
A functional interaction between the human papillomavirus 16 transcription/replication factor E2 and the DNA damage response protein TopBP1
J. Biol. Chem.
(2002)

A. Kumagai

TopBP1 activates the ATR-ATRIP complex

Cell

(2006)

C.M. Ulane et al.

Paramyxoviruses SV5 and HPIV2 assemble STAT protein ubiquitin ligase complexes from cellular components

Virology

(2002)

A.T. Lee

The hepatitis B virus X protein sensitizes HepG2 cells to UV light-induced DNA damage

J. Biol. Chem.

(2005)

M.K. Lewinski et al.

Retroviral DNA integration–mechanism and consequences

Adv. Genet.

(2005)

L.C. Mulder

Interaction of HIV-1 integrase with DNA repair protein hRad18

J. Biol. Chem.

(2002)

R.S. Pitcher

Mycobacteriophage exploit NHEJ to facilitate genome circularization

Mol. Cell

(2006)

T. Lindahl

Instability and decay of the primary structure of DNA

Nature

(1993)

A. Sancar

Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints

Annu. Rev. Biochem.

(2004)

A. Takaoka

Integration of interferon-α/β signalling to p53 responses in tumour suppression and antiviral defence

Nature

(2003)

C. Boutell et al.

Herpes simplex virus type 1 infection induces the stabilization of p53 in a USP7- and ATM-independent manner

J. Virol.

(2004)

C.E. Lilley

DNA repair proteins affect the lifecycle of herpes simplex virus 1

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

(2005)

D.E. Wilkinson et al.

Recruitment of cellular recombination and repair proteins to sites of herpes simplex virus type 1 DNA replication is dependent on the composition of viral proteins within prereplicative sites and correlates with the induction of the DNA damage response

J. Virol.

(2004)

J. Dahl

Induction and utilization of an ATM signaling pathway by polyomavirus

J. Virol.

(2005)

T.J. Taylor et al.

Proteomics of herpes simplex virus replication compartments: association of cellular DNA replication, repair, recombination, and chromatin remodeling proteins with ICP8

Relocalization of the Mre11-Rad50-Nbs1 complex by the adenovirus E4 ORF3 protein is required for viral replication

J. Virol.

(2005)

Cited by (180)

RNA polymerase II subunit modulation during viral infection and cellular stress
2022, Current Opinion in Virology
Control of gene expression, including transcription, is central in dictating the outcome of viral infection. One of the profound alterations induced by viruses is modification to the integrity and function of eukaryotic RNA polymerase II (Pol II). Here, we discuss how infection perturbs the Pol II complex by altering subunit phosphorylation and turnover, as well as how cellular genotoxic stress (e.g. DNA damage) elicits similar outcomes. By highlighting emerging parallels and differences in Pol II control during viral infection and abiotic stress, we hope to bolster identification of pathways that target Pol II and regulate the transcriptome.
Viral targeting of glioblastoma stem cells with patient-specific genetic and post-translational p53 deregulations
2021, Cell Reports
Cancer therapy urges targeting of malignant subsets within self-renewing heterogeneous stem cell populations. We dissect the genetic and functional heterogeneity of human glioblastoma stem cells (GSCs) within patients by their innate responses to non-pathogenic mouse parvoviruses that are tightly restrained by cellular physiology. GSC neurospheres accumulate assembled capsids but restrict viral NS1 cytotoxic protein expression by an innate PKR/eIF2α-P response counteractable by electric pulses. NS1 triggers a comprehensive DNA damage response involving cell-cycle arrest, neurosphere disorganization, and bystander disruption of GSC-derived brain tumor architecture in rodent models. GSCs and cancer cell lines permissive to parvovirus genome replication require p53-Ser15 phosphorylation (Pp53S15). NS1 expression is enhanced by exogeneous Pp53S15 induction but repressed by wtp53. Consistently, patient-specific GSC subpopulations harboring p53 gain-of-function mutants and/or Pp53S15 are selective viral targets. This study provides a molecular foundation for personalized biosafe viral therapies against devastating glioblastoma and other cancers with deregulated p53 signaling.
Antiviral drug screen identifies DNA-damage response inhibitor as potent blocker of SARS-CoV-2 replication
2021, Cell Reports
SARS-CoV-2 has currently precipitated the COVID-19 global health crisis. We developed a medium-throughput drug-screening system and identified a small-molecule library of 34 of 430 protein kinase inhibitors that were capable of inhibiting the SARS-CoV-2 cytopathic effect in human epithelial cells. These drug inhibitors are in various stages of clinical trials. We detected key proteins involved in cellular signaling pathways mTOR-PI3K-AKT, ABL-BCR/MAPK, and DNA-damage response that are critical for SARS-CoV-2 infection. A drug-protein interaction-based secondary screen confirmed compounds, such as the ATR kinase inhibitor berzosertib and torin2 with anti-SARS-CoV-2 activity. Berzosertib exhibited potent antiviral activity against SARS-CoV-2 in multiple cell types and blocked replication at the post-entry step. Berzosertib inhibited replication of SARS-CoV-1 and the Middle East respiratory syndrome coronavirus (MERS-CoV) as well. Our study highlights key promising kinase inhibitors to constrain coronavirus replication as a host-directed therapy in the treatment of COVID-19 and beyond as well as provides an important mechanism of host-pathogen interactions.
The Global Phosphorylation Landscape of SARS-CoV-2 Infection
2020, Cell
Citation Excerpt :
Here the CK2 inhibitor silmitasertib displayed robust antiviral activity, suggesting a role of this kinase in regulating the SARS-CoV-2 life cycle. In addition, kinase activity profiling analysis shows that CDK1/2 activities are significantly reduced by SARS-CoV-2 infection, leading to a S/G2 phase arrest that is similar to infectious bronchitis virus (IBV), a prototypical coronavirus (Dove et al., 2006; Li et al., 2007a), and other RNA viruses (Lilley et al., 2007; Ariumi et al., 2008). Arresting cells in S/G2 phase may provide benefits for viral replication and progeny production by ensuring an abundant supply of nucleotides and other essential host DNA repair/replication proteins (Chaurushiya and Weitzman 2009).
The causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions and killed hundreds of thousands of people worldwide, highlighting an urgent need to develop antiviral therapies. Here we present a quantitative mass spectrometry-based phosphoproteomics survey of SARS-CoV-2 infection in Vero E6 cells, revealing dramatic rewiring of phosphorylation on host and viral proteins. SARS-CoV-2 infection promoted casein kinase II (CK2) and p38 MAPK activation, production of diverse cytokines, and shutdown of mitotic kinases, resulting in cell cycle arrest. Infection also stimulated a marked induction of CK2-containing filopodial protrusions possessing budding viral particles. Eighty-seven drugs and compounds were identified by mapping global phosphorylation profiles to dysregulated kinases and pathways. We found pharmacologic inhibition of the p38, CK2, CDK, AXL, and PIKFYVE kinases to possess antiviral efficacy, representing potential COVID-19 therapies.
Adenovirus oncoprotein E4orf6 triggers Cullin5 neddylation to activate the CLR5 E3 ligase for p53 degradation
2019, Biochemical and Biophysical Research Communications
The human adenovirus oncoprotein E4orf6 hijacks intracellular Cullin 5-based E3 ubiquitin ligases (CRL5s) to induce the degradation of host proteins, including p53, that impede efficient viral replication. The complex also relies on another viral protein, E1B55K, to recruit substrates for ubiquitination. However, the determinants of adenoviral E4orf6-CRL5 E3 ligase-mediated p53 degradation in the scaffolding protein Cullin5 remain rarely investigated. Here, we demonstrated that the viral protein E4orf6 triggered relocalization of the Cullin5 protein from the cytoplasm to the nucleus and induced activation of the CRL5 E3 ligase via facilitating neddylation. The expression of the deneddylase SENP8/Den1 was significantly downregulated by E4orf6. We then identified SENP8 as a natural restriction factor for E4orf6-induced p53 degradation. Furthermore, our results indicated that the NEDD8-conjugating E2 enzyme UBE2M was essential for E4orf6-mediated p53 degradation and that its dominant negative mutant UBE2M C111S dramatically blocked E4orf6 functions. The Nedd8-activating enzyme inhibitor MLN4924 decreased E4orf6-induced neddylation of the cullin5 protein and subsequently suppressed p53 degradation. Collectively, our findings illuminate the strategy by which this viral oncoprotein specifically utilizes the neddylation pathway to activate host CRL E3 ligases to degrade host restriction factors. Disrupting this post-translational modification is an attractive pharmacological intervention against human adenoviruses.
The effect of mesenchymal stem cells administration on DNA repair gene expressions in critically ill COVID-19 patients: prospective controlled study
2024, Nucleosides, Nucleotides and Nucleic Acids

View all citing articles on Scopus

View full text

Trends in Microbiology

ReviewUsing or abusing: viruses and the cellular DNA damage response

Section snippets

The cellular DNA damage response

Viruses and the cellular DNA repair machinery

Consequences for the cell

Consequences for the virus

Concluding remarks

Acknowledgements

Cell

DNA Repair (Amst.)

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Virology

Virology

J. Biol. Chem.

Cell

Virology

J. Biol. Chem.

Adv. Genet.

J. Biol. Chem.

Mol. Cell

Instability and decay of the primary structure of DNA

Nature

Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints

Annu. Rev. Biochem.

Integration of interferon-α/β signalling to p53 responses in tumour suppression and antiviral defence

Nature

Herpes simplex virus type 1 infection induces the stabilization of p53 in a USP7- and ATM-independent manner

J. Virol.

DNA repair proteins affect the lifecycle of herpes simplex virus 1

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

Recruitment of cellular recombination and repair proteins to sites of herpes simplex virus type 1 DNA replication is dependent on the composition of viral proteins within prereplicative sites and correlates with the induction of the DNA damage response

J. Virol.

Induction and utilization of an ATM signaling pathway by polyomavirus

J. Virol.

Proteomics of herpes simplex virus replication compartments: association of cellular DNA replication, repair, recombination, and chromatin remodeling proteins with ICP8

J. Virol.

Potential role for p53 in the permissive life cycle of human cytomegalovirus

J. Virol.

Retroviral DNA integration and the DNA damage response

Cell Death Differ.

A role for DNA-PK in retroviral DNA integration

Science

Suppression of HIV-1 infection by a small molecule inhibitor of the ATM kinase

Nat. Cell Biol.

Caffeine inhibits human immunodeficiency virus type 1 transduction of nondividing cells

J. Virol.

The role of DNA recombination in herpes simplex virus DNA replication

IUBMB Life

Activation of the ATR pathway by human immunodeficiency virus type 1 Vpr involves its direct binding to chromatin in vivo

J. Virol.

Human immunodeficiency virus type 1 vpr induces DNA replication stress in vitro and in vivo

J. Virol.

Wortmannin potentiates integrase-mediated killing of lymphocytes and reduces the efficiency of stable transduction by retroviruses

Mol. Cell. Biol.

Evidence that the retroviral DNA integration process triggers an ATR-dependent DNA damage response

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

Viral transport of DNA damage that mimics a stalled replication fork

J. Virol.

How adeno-associated virus Rep78 protein arrests cells completely in S phase

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

Adenovirus oncoproteins inactivate the Mre11-Rad50-NBS1 DNA repair complex

Nature

Adenovirus type 5 E4orf3 protein targets the Mre11 complex to cytoplasmic aggresomes

J. Virol.

Relocalization of the Mre11-Rad50-Nbs1 complex by the adenovirus E4 ORF3 protein is required for viral replication

J. Virol.

Review
Using or abusing: viruses and the cellular DNA damage response