Roles of ATM and ATR-mediated DNA damage responses during lytic BK polyomavirus infection

BK polyomavirus (BKPyV) is an emerging pathogen whose reactivation causes severe disease in transplant patients. Unfortunately, there is no specific anti-BKPyV treatment available, and host cell components that affect the infection outcome are not well characterized. In this report, we examined the...

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Bibliographic Details
Published in:PLoS pathogens 2012-08, Vol.8 (8), p.e1002898-e1002898
Main Authors: Jiang, Mengxi, Zhao, Linbo, Gamez, Monica, Imperiale, Michael J
Format: Article
Language:English
Subjects:
Ataxia Telangiectasia Mutated Proteins - genetics
Ataxia Telangiectasia Mutated Proteins - metabolism
Biology
BK Virus - genetics
BK Virus - physiology
Cell Cycle
Cells, Cultured
Checkpoint Kinase 2 - genetics
Checkpoint Kinase 2 - metabolism
Deoxyribonucleic acid
DNA
DNA Damage
DNA repair
DNA Replication
Gene Knockdown Techniques
Health aspects
Histones - genetics
Histones - metabolism
Humans
Models, Molecular
Physiological aspects
Polyoma virus
Polyomavirus Infections - virology
Polyploidy
Proteins
RNA, Small Interfering
Signal Transduction
Transplants & implants
Tumor Virus Infections - virology
Virulence (Microbiology)
Virus Replication
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Summary:BK polyomavirus (BKPyV) is an emerging pathogen whose reactivation causes severe disease in transplant patients. Unfortunately, there is no specific anti-BKPyV treatment available, and host cell components that affect the infection outcome are not well characterized. In this report, we examined the relationship between BKPyV productive infection and the activation of the cellular DNA damage response (DDR) in natural host cells. Our results showed that both the ataxia-telangiectasia mutated (ATM)- and ATM and Rad-3-related (ATR)-mediated DDR were activated during BKPyV infection, accompanied by the accumulation of polyploid cells. We assessed the involvement of ATM and ATR during infection using small interfering RNA (siRNA) knockdowns. ATM knockdown did not significantly affect viral gene expression, but reduced BKPyV DNA replication and infectious progeny production. ATR knockdown had a slightly more dramatic effect on viral T antigen (TAg) and its modified forms, DNA replication, and progeny production. ATM and ATR double knockdown had an additive effect on DNA replication and resulted in a severe reduction in viral titer. While ATM mainly led to the activation of pChk2 and ATR was primarily responsible for the activation of pChk1, knockdown of all three major phosphatidylinositol 3-kinase-like kinases (ATM, ATR, and DNA-PKcs) did not abolish the activation of γH2AX during BKPyV infection. Finally, in the absence of ATM or ATR, BKPyV infection caused severe DNA damage and aberrant TAg staining patterns. These results indicate that induction of the DDR by BKPyV is critical for productive infection, and that one of the functions of the DDR is to minimize the DNA damage which is generated during BKPyV infection.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1002898