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
1 Division of Infectious Diseases – Center for Human Virology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
2 Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan
3 Division of Endocrinology, Thomas Jefferson University, Philadelphia, USA
4 Kimmel Cancer Center, Immunology Program, Thomas Jefferson University, Philadelphia, PA, USA
5 704G Abramson Research Center, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA
Virology Journal 2008, 5:11 doi:10.1186/1743-422X-5-11Published: 22 January 2008
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.