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Journal of Virology, October 2008, p. 9639-9646, Vol. 82, No. 19
0022-538X/08/$08.00+0     doi:10.1128/JVI.00351-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The DNA Damage Sensors Ataxia-Telangiectasia Mutated Kinase and Checkpoint Kinase 2 Are Required for Hepatitis C Virus RNA Replication{triangledown}

Yasuo Ariumi,1 Misao Kuroki,1 Hiromichi Dansako,1 Ken-Ichi Abe,1 Masanori Ikeda,1 Takaji Wakita,2 and Nobuyuki Kato1*

Department of Molecular Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Okayama 700-8558, Japan,1 Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan2

Received 18 February 2008/ Accepted 18 July 2008

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 replicon 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.

* Corresponding author. Mailing address: Department of Molecular Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Okayama 700-8558, Japan. Phone: 81 86 235 7385. Fax: 81 86 235 7392. E-mail: nkato{at}md.okayama-u.ac.jp

{triangledown} Published ahead of print on 30 July 2008.

Journal of Virology, October 2008, p. 9639-9646, Vol. 82, No. 19
0022-538X/08/$08.00+0     doi:10.1128/JVI.00351-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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