IRS‐1–Rad51 nuclear interaction sensitizes JCV T‐antigen positive medulloblastoma cells to genotoxic treatment

Trojanek, Joanna; Ho, Thu; Croul, Sidney; Wang, Jin Ying; Chintapalli, Janaki; Koptyra, Mateusz; Giordano, Antonio; Khalili, Kamel; Reiss, Krzysztof

doi:10.1002/ijc.21828

Cited by 19 publications

(27 citation statements)

References 51 publications

(72 reference statements)

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“…It is thought that this effect is caused by TAg binding to RPA and preventing RPA from localizing to repair foci following DNA damage. Similar sensitization to DNA damage has been observed with SV40 and JCPyV (36,37). Therefore, in addition to a lack of viral DNA replication, another possible reason that the DDR is not activated during D501A mutant virus infection is that certain DDR signaling proteins are being sequestered by TAg.…”

Section: Discussionsupporting

confidence: 59%

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

Verhalen

Justice

Imperiale

et al. 2015

J Virol

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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...

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Section: Discussionsupporting

confidence: 59%

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

Verhalen

Justice

Imperiale

et al. 2015

J Virol

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“…In the nucleus, IRS-1 interacts with Rad51 and negatively interferes with HRR. The molecular basis for LT-ag-induced nuclear translocation of IRS-1 and IRS-1-mediated inhibition of HRR remains to be solved [34,35]. Finally, LT-ag may induce genomic instability through elimination of the small GTPase Ran .…”

Section: Effect On Chromosome Fidelitymentioning

confidence: 95%

Oncogenic potentials of the human polyomavirus regulatory proteins

Moens

Ghelue

Johannessen

2007

Cell. Mol. Life Sci.

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The polyomaviruses BK, JC and SV40 are common in the human population. Their DNA genomes encode large T-antigen, small t-antigen, agnoprotein, and the capsid proteins VP1-3. Studies with these viruses have contributed extensively to the understanding of processes such as replication, transcriptional and posttranscriptional regulation, and cell cycle control. All three viruses can transform human cells in vitro, can induce tumours in animal models, and are strongly association with certain human cancers. It is generally assumed that large T-antigen is the major protein involved in neoplastic processes and that large T-antigen predominantly exerts its effect through deregulation of the tumour suppressors p53 and the retinoblastoma family members. However, additional properties of large T-antigen as well as the other viral proteins contribute to oncogenic processes. This review presents the different mechanisms by which the polyomavirus proteins can induce transformation and discusses which mechanisms may be operational in polyomavirus-positive cancers.

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“…In addition, effects of cisplatin and ICI182,780 were evaluated in cells replicating DNA (10%FBS), therefore the cisplatin treatment which primarily generates DNA-adducts and oxidative DNA damage [24], [25], [26] is also expected to cause DNA double strand breaks (DSBs) [27], [28], [29]. This happens when the replication forks are stalled on the cisplatin-induced primary DNA lesions [29], [30], [31]. We have used neutral comet assay to evaluate DSBs formation in Daoy cells treated with cisplatin [32].…”

Section: Resultsmentioning

confidence: 99%

Inhibition of ERβ Induces Resistance to Cisplatin by Enhancing Rad51–Mediated DNA Repair in Human Medulloblastoma Cell Lines

et al. 2012

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Cisplatin is one of the most widely used and effective anticancer drugs against solid tumors including cerebellar tumor of the childhood, Medulloblastoma. However, cancer cells often develop resistance to cisplatin, which limits therapeutic effectiveness of this otherwise effective genotoxic drug. In this study, we demonstrate that human medulloblastoma cell lines develop acute resistance to cisplatin in the presence of estrogen receptor (ER) antagonist, ICI182,780. This unexpected finding involves a switch from the G2/M to G1 checkpoint accompanied by decrease in ATM/Chk2 and increase in ATR/Chk1 phosphorylation. We have previously reported that ERβ, which is highly expressed in medulloblastomas, translocates insulin receptor substrate 1 (IRS-1) to the nucleus, and that nuclear IRS-1 binds to Rad51 and attenuates homologous recombination directed DNA repair (HRR). Here, we demonstrate that in the presence of ICI182,780, cisplatin-treated medulloblastoma cells show recruitment of Rad51 to the sites of damaged DNA and increase in HRR activity. This enhanced DNA repair during the S phase preserved also clonogenic potential of medulloblastoma cells treated with cisplatin. In conclusion, inhibition of ERβ considered as a supplemental anticancer therapy, has been found to interfere with cisplatin–induced cytotoxicity in human medulloblastoma cell lines.

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IRS‐1–Rad51 nuclear interaction sensitizes JCV T‐antigen positive medulloblastoma cells to genotoxic treatment

Cited by 19 publications

References 51 publications

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

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

Oncogenic potentials of the human polyomavirus regulatory proteins

Inhibition of ERβ Induces Resistance to Cisplatin by Enhancing Rad51–Mediated DNA Repair in Human Medulloblastoma Cell Lines

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