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Journal of Virology, August 2004, p. 8573-8581, Vol. 78, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.16.8573-8581.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Evidence that Stable Retroviral Transduction and Cell Survival following DNA Integration Depend on Components of the Nonhomologous End Joining Repair Pathway

René Daniel,1,{dagger} James G. Greger,1 Richard A. Katz,1 Konstantin D. Taganov,1 Xiaoyun Wu,2 John C. Kappes,2 and Anna Marie Skalka1*

Fox Chase Cancer Center, Institute for Cancer Research, Philadelphia, Pennsylvania 19111-2497,1 Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294-00072

Received 31 October 2003/ Accepted 5 April 2004

We have previously reported several lines of evidence that support a role for cellular DNA repair systems in completion of the retroviral DNA integration process. Failure to repair an intermediate in the process of integrating viral DNA into host DNA appears to trigger growth arrest or death of a large percentage of infected cells. Cellular proteins involved in the nonhomologous end joining (NHEJ) pathway (DNA-PKCS) and the damage-signaling kinases (ATM and ATR) have been implicated in this process. However, some studies have suggested that NHEJ proteins may not be required for the completion of lentiviral DNA integration. Here we provide additional evidence that NHEJ proteins are required for stable transduction by human immunodeficiency type 1 (HIV-1)-based vectors. Our analyses with two different reporters show that the number of stably transduced DNA-PKCS-deficient scid fibroblasts was reduced by 80 to 90% compared to the number of control cells. Furthermore, transduction efficiency can be restored to wild-type levels in scid cells that are complemented with a functional DNA-PKCS gene. The efficiency of stable transduction by an HIV-1-based vector is also reduced upon infection of Xrcc4 and ligase IV-deficient cells, implying a role for these components of the NHEJ repair pathway. Finally, we show that cells deficient in ligase IV are killed by infection with an integrase-competent but not an integrase-deficient HIV-1 vector. Results presented in this study lend further support to a general role for the NHEJ DNA repair pathway in completion of the retroviral DNA integration process.

* Corresponding author. Mailing address: Fox Chase Cancer Center, Institute for Cancer Research, 333 Cottman Ave., Philadelphia, PA 19111-2497. Phone: (215) 728-2490. Fax: (215) 728-2778. E-mail: am_skalka{at}fccc.edu.

{dagger} Present address: Thomas Jefferson University, Philadelphia, PA 19107-5587.

Journal of Virology, August 2004, p. 8573-8581, Vol. 78, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.16.8573-8581.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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