The DNA damage sensors ataxia-telangiectasia mutated kinase and checkpoint kinase 2 are required for hepatitis C virus RNA replication

Yasuo Ariumi, Misao Kuroki, Hiromichi Dansako, Ken Ichi Abe, Masanori Ikeda, Takaji Wakita, Nobuyuki Kato

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Cellular responses to DNA damage are crucial for maintaining genome integrity, virus infection, and preventing the development of cancer. Hepatitis C virus (HCV) infection and the expression of the HCV nonstructural protein NS3 and core protein have been proposed as factors involved in the induction of double-stranded DNA breaks and enhancement of the mutation frequency of cellular genes. Since DNA damage sensors, such as the ataxia-telangiectasia mutated kinase (ATM), ATM- and Rad3-related kinase (ATR), poly(ADP-ribose) polymerase 1 (PARP-1), and checkpoint kinase 2 (Chk2), play central roles in the response to genotoxic stress, we hypothesized that these sensors might affect HCV replication. To test this hypothesis, we examined the level of HCV RNA in HuH-7-derived cells stably expressing short hairpin RNA targeted to ATM, ATR, PARP-1, or Chk2. Consequently, we found that replication of both genome-length HCV RNA (HCV-O, genotype 1b) and the subgenomic repli con RNA were notably suppressed in ATM- or Chk2-knockdown cells. In addition, the RNA replication of HCV-JFH1 (genotype 2a) and the release of core protein into the culture supernatants were suppressed in these knockdown cells after inoculation of the cell culture-generated HCV. Consistent with these observations, ATM kinase inhibitor could suppress the HCV RNA replication. Furthermore, we observed that HCV NS3-NS4A interacted with ATM and that HCV NS5B interacted with both ATM and Chk2. Taken together, these results suggest that the ATM signaling pathway is critical for HCV RNA replication and may represent a novel target for the clinical treatment of patients with chronic hepatitis C.

Original languageEnglish
Pages (from-to)9639-9646
Number of pages8
JournalJournal of Virology
Volume82
Issue number19
DOIs
Publication statusPublished - Oct 2008

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Checkpoint Kinase 2
Ataxia Telangiectasia
Hepatitis C virus
Virus Replication
Hepacivirus
DNA damage
DNA Damage
phosphotransferases (kinases)
Phosphotransferases
RNA
Virus Diseases
NAD ADP-ribosyltransferase
RNA replication
Genotype
Genome
Critical Pathways
Double-Stranded DNA Breaks
chronic hepatitis C
Chronic Hepatitis C
Mutation Rate

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

The DNA damage sensors ataxia-telangiectasia mutated kinase and checkpoint kinase 2 are required for hepatitis C virus RNA replication. / Ariumi, Yasuo; Kuroki, Misao; Dansako, Hiromichi; Abe, Ken Ichi; Ikeda, Masanori; Wakita, Takaji; Kato, Nobuyuki.

In: Journal of Virology, Vol. 82, No. 19, 10.2008, p. 9639-9646.

Research output: Contribution to journalArticle

Ariumi, Yasuo ; Kuroki, Misao ; Dansako, Hiromichi ; Abe, Ken Ichi ; Ikeda, Masanori ; Wakita, Takaji ; Kato, Nobuyuki. / The DNA damage sensors ataxia-telangiectasia mutated kinase and checkpoint kinase 2 are required for hepatitis C virus RNA replication. In: Journal of Virology. 2008 ; Vol. 82, No. 19. pp. 9639-9646.
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