Suppression of retroviral infection by the RAD52 DNA repair protein.
Reverse transcription of retroviral RNA into linear double-stranded DNA and its integration into the host cell genome are essential steps in the retroviral life cycle. The nonhomologous end-joining (NHEJ) DNA repair pathway has been implicated in protecting cells from retrovirus-induced apoptosis caused by strand breaks in host cell DNA or unintegrated linear viral DNA. In eukaryotes, both the NHEJ and homologous recombination (HR) pathways play important roles in repairing DNA double-strand breaks. Here we show that the HR repair protein RAD52 modulates the outcome of recombinant HIV-l vector infection by markedly reducing the efficiency of productive integration events. Increased retroviral integration is the first major phenotype described for a RAD52 deficiency in mammalian cells. Mutations in other HR proteins (XRCC2, XRCC3 and BRCA2) do not markedly affect retroviral transduction rates, suggesting that the HR repair pathway per se does not influence retroviral infection. Instead, the mechanism of attenuation of retroviral infection by RAD52 appears to be based upon competition between the RAD52 protein and active integration complexes for the retroviral cDNA genome.
KuDOS Pharmaceuticals Limited, 327 Cambridge Science Park, Cambridge, UK.
Alan
A
Lau
Roland
R
Kanaar
Stephen P
SP
Jackson
Mark J
MJ
O'Connor
D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D017209:Apoptosis; D002460:Cell Line; D004260:DNA Repair; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D000072200:Ku Autoantigen; D051379:Mice; D018345:Mice, Knockout; D051721:Rad52 DNA Repair and Recombination Protein; D012190:Retroviridae / Q000235:genetics / Q000502:physiology*; D014161:Transduction, Genetic; D016662:Virus Integration / Q000502:physiology
D034961:Antigens, Nuclear; D004279:DNA, Viral; D004268:DNA-Binding Proteins; C497194:RAD52 protein, human; D051721:Rad52 DNA Repair and Recombination Protein; C497196:Rad52 protein, mouse; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen