Abstract
Replication of herpes simplex virus 1 is coupled to recombination, but the molecular mechanisms underlying this process are poorly characterized. The role of Rad51 and Rad52 recombinases in viral recombination was examined in human fibroblast cells 1BR.3.N (wild type) and in GM16097 with replication defects caused by mutations in DNA ligase I. Intermolecular recombination between viruses, tsS and tsK, harboring genetic markers gave rise to ∼17% recombinants in both cell lines. Knock-down of Rad51 and Rad52 by siRNA reduced production of recombinants to 11% and 5%, respectively, in wild type cells and to 3% and 5%, respectively, in GM16097 cells. The results indicate a specific role for Rad51 and Rad52 in recombination of replicating herpes simplex virus 1 DNA. Mixed infections using clinical isolates with restriction enzyme polymorphisms in the US4 and US7 genes revealed recombination frequencies of 0.7%/kbp in wild type cells and 4%/kbp in GM16097 cells. Finally, tandem repeats in the US7 gene remained stable upon serial passage, indicating a high fidelity of recombination in infected cells.
Highlights
Homologous recombination is increasingly recognized as a major mechanism for maintaining genetic diversity of viruses
Phylogenetic analyses of clinical herpes simplex virus 1 (HSV1) isolates have shown that homologous recombination occurs frequently and that this mechanism seems to be essential for HSV1 evolution, and for maintaining genomic integrity [1,2,3,4,5,6] Similar observations have been made for other alphaherpesviruses [7,8,9,10]
Role of Rad51 and Rad52 in HSV-1 recombination Existing results suggest a modest role for Rad51 during undisturbed DNA replication of the HSV-1 genome
Summary
Homologous recombination is increasingly recognized as a major mechanism for maintaining genetic diversity of viruses. Phylogenetic analyses of clinical herpes simplex virus 1 (HSV1) isolates have shown that homologous recombination occurs frequently and that this mechanism seems to be essential for HSV1 evolution, and for maintaining genomic integrity [1,2,3,4,5,6] Similar observations have been made for other alphaherpesviruses [7,8,9,10]. Homologous recombination is responsible for genomic isomerization occurring during HSV-1 replication [11]. The HSV-1 genome consists of two segments, designated unique long (UL) and unique short (US). The a sequences are sites for cleavage of concatemeric genomes into monomers, which will be packaged into virus particles. The genome isomers are found in equimolar ratios, reflecting a high frequency of homologous recombination
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