scholarly journals Baculovirus Infection Induces a DNA Damage Response That Is Required for Efficient Viral Replication

2011 ◽  
Vol 85 (23) ◽  
pp. 12547-12556 ◽  
Author(s):  
N. Huang ◽  
W. Wu ◽  
K. Yang ◽  
A. L. Passarelli ◽  
G. F. Rohrmann ◽  
...  
Keyword(s):  
Dna Damage ◽  
Viral Replication ◽  
Dna Damage Response ◽  
Baculovirus Infection ◽  
Damage Response ◽  
Efficient Viral Replication

scholarly journals γ-Herpesvirus Kinase Actively Initiates a DNA Damage Response by Inducing Phosphorylation of H2AX to Foster Viral Replication

2007 ◽  
Vol 1 (4) ◽  
pp. 275-286 ◽  
Author(s):  
Vera L. Tarakanova ◽  
Van Leung-Pineda ◽  
Seungmin Hwang ◽  
Chiao-Wen Yang ◽  
Katie Matatall ◽  
...  
Keyword(s):  
Dna Damage ◽  
Viral Replication ◽  
Dna Damage Response ◽  
Damage Response

scholarly journals Baculovirus F-Box Protein LEF-7 Modifies the Host DNA Damage Response To Enhance Virus Multiplication

2013 ◽  
Vol 87 (23) ◽  
pp. 12592-12599 ◽  
Author(s):  
Jonathan K. Mitchell ◽  
Nathaniel M. Byers ◽  
Paul D. Friesen
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Viral Gene Expression ◽  
Virus Multiplication ◽  
Site Directed Mutagenesis ◽  
Viral Gene ◽  
Content Type ◽  
Baculovirus Infection ◽  
Damage Response ◽  
F Box Protein

The DNA damage response (DDR) of a host organism represents an effective antiviral defense that is frequently manipulated and exploited by viruses to promote multiplication. We report here that the large DNA baculoviruses, which require host DDR activation for optimal replication, encode a conserved replication factor, LEF-7, that manipulates the DDR via a novel mechanism. LEF-7 suppresses DDR-induced accumulation of phosphorylated host histone variant H2AX (γ-H2AX), a critical regulator of the DDR. LEF-7 was necessary and sufficient to block γ-H2AX accumulation caused by baculovirus infection or DNA damage induced by means of pharmacological agents. Deletion of LEF-7 from the baculovirus genome allowed γ-H2AX accumulation during virus DNA synthesis and impaired both very late viral gene expression and production of infectious progeny. Thus, LEF-7 is essential for efficient baculovirus replication. We determined that LEF-7 is a nuclear F-box protein that interacts with host S-phase kinase-associated protein 1 (SKP1), suggesting that LEF-7 acts as a substrate recognition component of SKP1/Cullin/F-box (SCF) complexes for targeted protein polyubiquitination. Site-directed mutagenesis demonstrated that LEF-7's N-terminal F-box is necessary for γ-H2AX repression andAutographa californicamultiple nucleopolyhedrovirus (AcMNPV) replication events. We concluded that LEF-7 expedites virus replication most likely by selective manipulation of one or more host factors regulating the DDR, including γ-H2AX. Thus, our findings indicate that baculoviruses utilize a unique strategy among viruses for hijacking the host DDR by using a newly recognized F-box protein.

scholarly journals Viral DNA Replication-Dependent DNA Damage Response Activation during BK Polyomavirus Infection

2015 ◽  
Vol 89 (9) ◽  
pp. 5032-5039 ◽  
Author(s):  
Brandy Verhalen ◽  
Joshua L. Justice ◽  
Michael J. Imperiale ◽  
Mengxi Jiang
Keyword(s):  
Bone Marrow ◽  
Dna Damage ◽  
Viral Replication ◽  
Dna Damage Response ◽  
Marrow Transplant ◽  
Viral Dna ◽  
Viral Dna Replication ◽  
Transplant Patients ◽  
Bk Polyomavirus ◽  
Damage Response

ABSTRACTBK polyomavirus (BKPyV) reactivation is associated with severe human disease in kidney and bone marrow transplant patients. The interplay between viral and host factors that regulates the productive infection process remains poorly understood. We have previously reported that the cellular DNA damage response (DDR) is activated upon lytic BKPyV infection and that its activation is required for optimal viral replication in primary kidney epithelial cells. In this report, we set out to determine what viral components are responsible for activating the two major phosphatidylinositol 3-kinase-like kinases (PI3KKs) involved in the DDR: ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3-related (ATR) kinase. Using a combination of UV treatment, lentivirus transduction, and mutant virus infection experiments, our results demonstrate that neither the input virus nor the expression of large T antigen (TAg) alone is sufficient to trigger the activation of ATM or ATR in our primary culture model. Instead, our data suggest that the activation of both the ATM- and ATR-mediated DDR pathways is linked to viral DNA replication. Intriguingly, a TAg mutant virus that is unable to activate the DDR causes substantial host DNA damage. Our study provides insight into how DDRs are activated by polyomaviruses in primary cells with intact cell cycle checkpoints and how the activation might be linked to the maintenance of host genome stability.IMPORTANCEPolyomaviruses are opportunistic pathogens that are associated with several human diseases under immunosuppressed conditions. BK polyomavirus (BKPyV) affects mostly kidney and bone marrow transplant patients. The detailed replication mechanism of these viruses remains to be determined. We have previously reported that BKPyV activates the host DNA damage response (DDR), a response normally used by the host cell to combat genotoxic stress, to aid its own replication. In this study, we identified that the trigger for DDR activation is viral replication. Furthermore, we show that the virus is able to cause host DNA damage in the absence of viral replication and DDR activation. These results suggest an intricate relationship between viral replication, DDR activation, and host genome instability.

scholarly journals Differential Requirements of the C Terminus of Nbs1 in Suppressing Adenovirus DNA Replication and Promoting Concatemer Formation

2008 ◽  
Vol 82 (17) ◽  
pp. 8362-8372 ◽  
Author(s):  
Seema S. Lakdawala ◽  
Rachel A. Schwartz ◽  
Kevin Ferenchak ◽  
Christian T. Carson ◽  
Brian P. McSharry ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Viral Replication ◽  
Dna Damage Response ◽  
Viral Genomes ◽  
Mrn Complex ◽  
E4 Region ◽  
C Terminus ◽  
Damage Response ◽  
Cellular Dna

ABSTRACT Adenoviruses (Ad) with the early region E4 deleted (E4-deleted virus) are defective for DNA replication and late protein synthesis. Infection with E4-deleted viruses results in activation of a DNA damage response, accumulation of cellular repair factors in foci at viral replication centers, and joining together of viral genomes into concatemers. The cellular DNA repair complex composed of Mre11, Rad50, and Nbs1 (MRN) is required for concatemer formation and full activation of damage signaling through the protein kinases Ataxia-telangiectasia mutated (ATM) and ATM-Rad3-related (ATR). The E4orf3 and E4orf6 proteins expressed from the E4 region of Ad type 5 (Ad5) inactivate the MRN complex by degradation and mislocalization, and prevent the DNA damage response. Here we investigated individual contributions of the MRN complex, concatemer formation, and damage signaling to viral DNA replication during infection with E4-deleted virus. Using virus mutants, short hairpin RNA knockdown and hypomorphic cell lines, we show that inactivation of MRN results in increased viral replication. We demonstrate that defective replication in the absence of E4 is not due to concatemer formation or DNA damage signaling. The C terminus of Nbs1 is required for the inhibition of Ad DNA replication and recruitment of MRN to viral replication centers. We identified regions of Nbs1 that are differentially required for concatemer formation and inhibition of Ad DNA replication. These results demonstrate that targeting of the MRN complex explains the redundant functions of E4orf3 and E4orf6 in promoting Ad DNA replication. Understanding how MRN impacts the adenoviral life cycle will provide insights into the functions of this DNA damage sensor.

scholarly journals Simian Virus 40 Large T Antigen Disrupts Genome Integrity and Activates a DNA Damage Response via Bub1 Binding

2008 ◽  
Vol 83 (1) ◽  
pp. 117-127 ◽  
Author(s):  
Jennifer Hein ◽  
Sergei Boichuk ◽  
Jiaping Wu ◽  
Yuan Cheng ◽  
Raimundo Freire ◽  
...  
Keyword(s):  
Dna Damage ◽  
Viral Replication ◽  
Dna Damage Response ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
T Antigen ◽  
Genome Integrity ◽  
Large T Antigen ◽  
Sv40 Large T Antigen ◽  
Damage Response

ABSTRACT Simian virus 40 (SV40) large T antigen (LT) is a multifunctional protein that is important for viral replication and oncogenic transformation. Previously, infection of monkey or human cells with SV40 was shown to lead to the induction of DNA damage response signaling, which is required for efficient viral replication. However, it was not clear if LT is sufficient to induce the damage response and, if so, what the genetic requirements and functional consequences might be. Here, we show that the expression of LT alone, without a replication origin, can induce key DNA damage response markers including the accumulation of γ-H2AX and 53BP1 in nuclear foci. Other DNA damage-signaling components downstream of ATM/ATR kinases were induced, including chk1 and chk2. LT also bound the Claspin mediator protein, which normally facilitates the ATR activation of chk1 and monitors cellular replication origins. Stimulation of the damage response by LT depends mainly on binding to Bub1 rather than to the retinoblastoma protein. LT has long been known to stabilize p53 despite functionally inactivating it. We show that the activation of a DNA damage response by LT via Bub1 appears to play a major role in p53 stabilization by promoting the phosphorylation of p53 at Ser15. Accompanying the DNA damage response, LT induces tetraploidy, which is also dependent on Bub1 binding. Taken together, our data suggest that LT, via Bub1 binding, breaches genome integrity mechanisms, leading to DNA damage responses, p53 stabilization, and tetraploidy.

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