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Copyright © 2008 Smith et al; licensee BioMed Central Ltd. Evidence that the Nijmegen breakage syndrome protein, an early sensor of double-strand DNA breaks (DSB), is involved in HIV-1 post-integration repair by recruiting the ataxia telangiectasia-mutated kinase in a process similar to, but distinct from, cellular DSB repair Johanna A Smith,1,5 Feng-Xiang Wang,1,5 Hui Zhang,1,5 Kou-Juey Wu,2,5 Kevin Jon Williams,1,3,5 and René Daniel  1,4,51Division of Infectious Diseases – Center for Human Virology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA 2Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan 3Division of Endocrinology, Thomas Jefferson University, Philadelphia, USA 4Kimmel Cancer Center, Immunology Program, Thomas Jefferson University, Philadelphia, PA, USA 5704G Abramson Research Center, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA Corresponding author.Johanna A Smith: Johanna.Smith/at/jefferson.edu; Feng-Xiang Wang: wangf/at/email.chop.edu; Hui Zhang: Hui.Zhang/at/jefferson.edu; Kou-Juey Wu: kjwu2/at/ym.edu.tw; Kevin Jon Williams: K_Williams/at/mail.jci.tju.edu; René Daniel: Rene.Daniel/at/jefferson.edu Received November 16, 2007; Accepted January 22, 2008. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. | ||||
Abstract Retroviral transduction involves integrase-dependent linkage of viral and host DNA that leaves an intermediate that requires post-integration repair (PIR). We and others proposed that PIR hijacks the host cell double-strand DNA break (DSB) repair pathways. Nevertheless, the geometry of retroviral DNA integration differs considerably from that of DSB repair and so the precise role of host-cell mechanisms in PIR remains unclear. In the current study, we found that the Nijmegen breakage syndrome 1 protein (NBS1), an early sensor of DSBs, associates with HIV-1 DNA, recruits the ataxia telangiectasia-mutated (ATM) kinase, promotes stable retroviral transduction, mediates efficient integration of viral DNA and blocks integrase-dependent apoptosis that can arise from unrepaired viral-host DNA linkages. Moreover, we demonstrate that the ATM kinase, recruited by NBS1, is itself required for efficient retroviral transduction. Surprisingly, recruitment of the ATR kinase, which in the context of DSB requires both NBS1 and ATM, proceeds independently of these two proteins. A model is proposed emphasizing similarities and differences between PIR and DSB repair. Differences between the pathways may eventually allow strategies to block PIR while still allowing DSB repair. | ||||
