title: 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.
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.
authors.affiliation: Division of Infectious Diseases - Center for Human Virology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. Johanna.Smith@jefferson.edu
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Smith
authors.forename: Feng-Xiang
authors.initials: FX
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Kou-Juey
authors.initials: KJ
authors.lastname: Wu
authors.forename: Kevin Jon
authors.initials: KJ
authors.lastname: Williams
authors.forename: René
authors.initials: R
authors.lastname: Daniel
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000502:physiology*; D004249:DNA Damage / Q000502:physiology; D004260:DNA Repair / Q000502:physiology*; D051747:DNA-Activated Protein Kinase / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015497:HIV-1 / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D049932:Nijmegen Breakage Syndrome; D009687:Nuclear Proteins / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051747:DNA-Activated Protein Kinase; D017346:Protein Serine-Threonine Kinases