Viral Interference with DNA Repair by Targeting of the Single-Stranded DNA Binding Protein RPA

Banerjee, Pubali; deJesus, Rowena; Gjoerup, Ole; Schaffhausen, Brian

doi:10.1371/journal.ppat.1003725

Cited by 16 publications

(12 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This observation suggests that recruitment of DDR proteins to replication centers is mediated through LT. The MuPyV LT may facilitate recruitment and activation of DDR protein through an interaction with the RPA complex or NBS1 (Banerjee, et al 2013, Wu, et al 2004). However, the increased viral DNA accumulation and the expansion of viral replication centers observed in WT and 808A infected cells is likely dependent on signaling pathways regulated by ST, including AKT or MAPK.…”

Section: Discussionmentioning

confidence: 99%

“…Large T-antigen (LT) drives cell cycle progression into S-phase through interactions with host proteins, such as phosphorylated retinoblastoma protein (Rb) (Sheng, et al 1997, Zalvide, et al 1998). Additionally, it is thought that LT binds to DDR proteins, including a component of the MRN complex, Nbs1, and the RPA complex to manipulate the host cell DDR to enhance viral DNA replication (Banerjee, et al 2013, Wu, et al 2004). …”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Activation of DNA damage repair pathways by murine polyomavirus

2016

View full text Add to dashboard Cite

Nuclear replication of DNA viruses activates DNA damage repair (DDR) pathways, which are thought to detect and inhibit viral replication. However, many DNA viruses also depend on these pathways in order to optimally replicate their genomes. We investigated the relationship between murine polyomavirus (MuPyV) and components of DDR signaling pathways including CHK1, CHK2, H2AX, ATR, and DNAPK. We found that recruitment and retention of DDR proteins at viral replication centers was independent of H2AX, as well as the viral small and middle T-antigens. Additionally, infectious virus production required ATR kinase activity, but was independent of CHK1, CHK2, or DNAPK signaling. ATR inhibition did not reduce the total amount of viral DNA accumulated, but affected the amount of virus produced, indicating a defect in virus assembly. These results suggest that MuPyV may utilize a subset of DDR proteins or non-canonical DDR signaling pathways in order to efficiently replicate and assemble.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Activation of DNA damage repair pathways by murine polyomavirus

2016

View full text Add to dashboard Cite

show abstract

“…It has been reported for mPyV that TAg can sensitize the cells to DNA-damaging conditions, such as UV or etoposide treatment (35). It is thought that this effect is caused by TAg binding to RPA and preventing RPA from localizing to repair foci following DNA damage.…”

Section: Discussionmentioning

confidence: 99%

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

Verhalen

Justice

Imperiale

et al. 2015

J Virol

View full text Add to dashboard Cite

BK 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. The BK polyomavirus (BKPyV) is a ubiquitous opportunistic human pathogen which causes severe disease in immunocompromised patients (1). BKPyV is thought to be acquired through the respiratory route during early childhood, and by adulthood, up to 90% of the general population becomes seropositive (2). Following primary exposure, the virus establishes a lifelong, subclinical, persistent infection in the genitourinary tract. BKPyV can reactivate from the persistent state under immunosuppressed conditions, most commonly in kidney transplant patients, resulting in viral shedding in urine or blood and, ultimately, polyomavirus-associated nephropathy, a significant cause of renal dysfunction (3). There are no FDA-approved therapies for BKPyV infection, and the usual treatment is to reduce immu...

show abstract

“…RPA is a heterotrimer complex (composed of RPA70, RPA32, and RPA14 subunits) that binds and stabilizes single-stranded DNA (ssDNA) during DNA replication and repair. LT binds the RPA70 subunit during PyV replication, which may contribute to efficient RPA loading onto ssDNA that emerges behind the LT helicase [38][39][40]. In addition to binding ssDNA, RPA also acts as a scaffold for DNA replication and repair factors.…”

Section: Introductionmentioning

confidence: 99%

Murine polyomavirus DNA transitions through spatially distinct nuclear replication subdomains during infection

Peters

Garcea

2020

PLoS Pathog

View full text Add to dashboard Cite

The replication of small DNA viruses requires both host DNA replication and repair factors that are often recruited to subnuclear domains termed viral replication centers (VRCs). Aside from serving as a spatial focus for viral replication, little is known about these dynamic areas in the nucleus. We investigated the organization and function of VRCs during murine polyomavirus (MuPyV) infection using 3D structured illumination microscopy (3D-SIM). We localized MuPyV replication center components, such as the viral large T-antigen (LT) and the cellular replication protein A (RPA), to spatially distinct subdomains within VRCs. We found that viral DNA (vDNA) trafficked sequentially through these subdomains post-synthesis, suggesting their distinct functional roles in vDNA processing. Additionally, we observed disruption of VRC organization and vDNA trafficking during mutant MuPyV infections or inhibition of DNA synthesis. These results reveal a dynamic organization of VRC components that coordinates virus replication.

show abstract

Viral Interference with DNA Repair by Targeting of the Single-Stranded DNA Binding Protein RPA

Cited by 16 publications

References 46 publications

Activation of DNA damage repair pathways by murine polyomavirus

Activation of DNA damage repair pathways by murine polyomavirus

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

Murine polyomavirus DNA transitions through spatially distinct nuclear replication subdomains during infection

Contact Info

Product

Resources

About