title: The role of DNA repair in herpesvirus pathogenesis.
abstract: In cells latently infected with a herpesvirus, the viral DNA is present in the cell nucleus, but it is not extensively replicated or transcribed. In this suppressed state the virus DNA is vulnerable to mutagenic events that affect the host cell and have the potential to destroy the virus' genetic integrity. Despite the potential for genetic damage, however, herpesvirus sequences are well conserved after reactivation from latency. To account for this apparent paradox, I have tested the idea that host cell-encoded mechanisms of DNA repair are able to control genetic damage to latent herpesviruses. Studies were focused on homologous recombination-dependent DNA repair (HR). Methods of DNA sequence analysis were employed to scan herpesvirus genomes for DNA features able to activate HR. Analyses were carried out with a total of 39 herpesvirus DNA sequences, a group that included viruses from the alpha-, beta- and gamma-subfamilies. The results showed that all 39 genome sequences were enriched in two or more of the eight recombination-initiating features examined. The results were interpreted to indicate that HR can stabilize latent herpesvirus genomes. The results also showed, unexpectedly, that repair-initiating DNA features differed in alpha- compared to gamma-herpesviruses. Whereas inverted and tandem repeats predominated in alpha-herpesviruses, gamma-herpesviruses were enriched in short, GC-rich initiation sequences such as CCCAG and depleted in repeats. In alpha-herpesviruses, repair-initiating repeat sequences were found to be concentrated in a specific region (the S segment) of the genome while repair-initiating short sequences were distributed more uniformly in gamma-herpesviruses. The results suggest that repair pathways are activated differently in alpha- compared to gamma-herpesviruses.
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Box 800734, Charlottesville, VA 2908, USA. Electronic address: jcb2g@virginia.edu.
authors.forename: Jay C
authors.initials: JC
authors.lastname: Brown
mesh_terms: D020862:GC Rich Sequence; D016679:Genome, Viral; D006564:Herpesviridae / Q000235:genetics* / Q000472:pathogenicity; D055029:Inverted Repeat Sequences; D018895:Microsatellite Repeats; D059767:Recombinational DNA Repair; D014774:Virulence / Q000235:genetics
keywords: DNA repair; DNA sequence repeats; Herpesvirus genome; Neuron