Abstract:
UNLABELLED:The DNA damage response (DDR) that evolved to repair host cell DNA damage also recognizes viral DNA entering the nucleus during infections. Here, we investigated the modulation of DDR signaling during de novo infection of primary endothelial cells by Kaposi's sarcoma-associated herpesvirus (KSHV). Phosphorylation of representative DDR-associated proteins, such as ataxia telangiectasia mutated (ATM) and H2AX, was induced as early as 30 min (0.5 h) postinfection and persisted during in vitro KSHV latency. Phosphorylated H2AX (γH2AX) colocalized at 30 min (0.5 h) with the KSHV genome entering the nuclei. Total H2AX protein levels also increased, and the increase was attributed to a decrease in degradative H2AX Lys48-linked polyubiquitination with a concomitant increase in Lys63-linked polyubiquitination that was shown to increase protein stability. ATM and H2AX phosphorylation and γH2AX nuclear foci were also induced by UV-inactivated KSHV, which ceased at later times of infection. Inhibition of ATM kinase activity by KU-55933 and H2AX knockdown by small interfering RNA significantly reduced the expression of the KSHV latency-associated nuclear antigen 1 (LANA-1; ORF73) and LANA-1 nuclear puncta. Knockdown of H2AX also resulted in a >80% reduction in the nuclear KSHV DNA copy numbers. Similar results were also observed in ATM-negative cells, although comparable levels of viral DNA entered ATM-negative and ATM-positive cell nuclei. In contrast, knockdown of CHK1 and CHK2 did not affect ORF73 expression. Collectively, these results demonstrate that KSHV induces ATM and H2AX, a selective arm of the DDR, for the establishment and maintenance of its latency during de novo infection of primary endothelial cells. IMPORTANCE:Eukaryotic cells mount a DNA damage response (DDR) to sense and repair different types of cellular DNA damage. In addition, DDR also recognizes exogenous genetic material, such as the viral DNA genome entering the nucleus during infections. The present study was undertaken to determine whether de novo Kaposi's sarcoma-associated herpesvirus (KSHV) infection modulates DDR. Our results demonstrate that early during de novo infection of primary endothelial cells, KSHV induces a selective arm of DDR signaling, such as the ATM kinase and its downstream target, H2AX, which are essential for KSHV's latent gene expression and the establishment of latency. These studies suggest that targeting ATM and H2AX could serve as an attractive strategy to block the establishment of KSHV latent infection and the associated malignancies.
journal_name
J Viroljournal_title
Journal of virologyauthors
Singh VV,Dutta D,Ansari MA,Dutta S,Chandran Bdoi
10.1128/JVI.03126-13subject
Has Abstractpub_date
2014-03-01 00:00:00pages
2821-34issue
5eissn
0022-538Xissn
1098-5514pii
JVI.03126-13journal_volume
88pub_type
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.65.1.464-467.1991
更新日期:1991-01-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.72.12.10189-10196.1998
更新日期:1998-12-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.66.11.6338-6352.1992
更新日期:1992-11-01 00:00:00
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pub_type: 杂志文章
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pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.73.6.4705-4712.1999
更新日期:1999-06-01 00:00:00
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doi:10.1128/JVI.55.1.133-139.1985
更新日期:1985-07-01 00:00:00
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doi:10.1128/JVI.29.2.529-535.1979
更新日期:1979-02-01 00:00:00
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pub_type: 杂志文章
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更新日期:2011-11-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
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更新日期:2014-08-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.36.1.171-180.1980
更新日期:1980-10-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.65.12.6553-6561.1991
更新日期:1991-12-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.2.9.937-943.1968
更新日期:1968-09-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.60.2.460-469.1986
更新日期:1986-11-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.68.4.2161-2168.1994
更新日期:1994-04-01 00:00:00
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更新日期:1985-12-01 00:00:00
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pub_type: 杂志文章
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pub_type: 杂志文章
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更新日期:2003-01-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
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更新日期:2001-12-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
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更新日期:1999-08-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.50.3.895-903.1984
更新日期:1984-06-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.64.10.5114-5122.1990
更新日期:1990-10-01 00:00:00
abstract::Three monkeypox virus (MPV) antibody-secreting murine monoclones were characterized as being of the immunoglobulin G1 isotype, gave a 4+ reaction in the indirect fluorescent-antibody test, gave a positive reaction in the enzyme immunoassay, and did not neutralize MPV. These monoclonal antibodies were determined by the...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.52.1.290-292.1984
更新日期:1984-10-01 00:00:00
abstract::The cellular tropism of the feline immunodeficiency virus (FIV) is affected by changes in variable region 3 (V3) of the surface (SU) envelope glycoprotein (Verschoor, E. J., et al., J. Virol. 69:4752-4757, 1995). By using high-dose DNA transfection, an FIV molecular clone with a non-CRFK-tropic V3 acquired the ability...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.71.9.7132-7135.1997
更新日期:1997-09-01 00:00:00
abstract::Lethal, amber mutations in T4 genes 46 and 47 cause incomplete degradation of host DNA, premature arrest of phage DNA synthesis, accumulation of abnormal DNA replication intermediates, and defective recombination. These phenotypes can be explained by the hypothesis that genes 46 and 47 control a DNA exonuclease, but i...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.40.1.65-77.1981
更新日期:1981-10-01 00:00:00
abstract::The two canine adenoviruses, infectious canine hepatitis (ICH) virus and infectious canine laryngotracheitis (ICL) virus (also designated as Toronto A26/61 virus), were studied with respect to their morphology and the biological properties of their soluble components. The two viruses were found to be composed of solub...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.5.4.507-512.1970
更新日期:1970-04-01 00:00:00
abstract::We previously reported that herpes simplex virus type 1 (HSV-1) can activate the stress-activated protein kinases (SAPKs) p38 and JNK. In the present study, we undertook a comprehensive and comparative analysis of the requirements for viral protein synthesis in the activation of JNK and p38. Infection with the UL36 mu...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.79.13.8348-8360.2005
更新日期:2005-07-01 00:00:00