Viral induction of site‐specific chromosome damage

Abstract

The advent of advanced cell culture and cytogenetics techniques in the 1950s opened a new avenue for research on the pathogenic interactions between animal viruses and their hosts. Studies of many viruses revealed their ability to nonspecifically induce cytogenetic damage to their host cell's chromosomes. However, only three viruses, the oncogenic adenoviruses, herpes simplex virus (HSV) and human cytomegalovirus (HCMV), have been found to cause non-random, site-specific chromosomal damage. Adenovirus (Ad) type 12 induces fragility at four distinct loci (RNU1, RNU2, RN5S and PSU1) in many different types of human cells. A common feature of these loci is that they contain a repeated array of transcriptionally active genes encoding small structural RNAs. Site-specific induction of breaks also requires the virally encoded E1B protein of M(r) 55000 and the C-terminus of the cellular p53 protein. Analysis of the induction of damage by HSV and HCMV necessitates consideration of several factors, including the strain of virus used, the timing of infection, the type of cell used, and the multiplicity of infection. Both HSV strains 1 and 2 are cytotoxic, although the former seems to be more proficient at inducing damage. At early times post infection, HSV induces breaks and specific uncoiling of the centromeres of chromosomes 1, 9 and 16. This is followed at later times by a more complete severing of all of the chromosomes, termed pulverisation. Damage by HSV requires viral entry and de novo viral protein synthesis, with immediate early viral proteins responsible for the induction of breaks and uncoiling and early gene products (most likely nucleases) involved in the extensive pulverisation seen later. HCMV has been studied primarily in permissive human fibroblasts. Its ability to induce specific damage in chromosome 1 at two loci, 1q21 and 1q42, was only recently revealed as the cells must be in S-phase when they are infected for the breaks to be observed. In contrast to adenovirus and HSV, HCMV induction of specific breakage requires only viral entry into the cell and not de novo viral protein expression. This latter point may be a factor in its ability to cause damage in the developing fetal brain, where the most severe clinical manifestations of congenital infection are observed.

Role of tumor invasiveness, the extracellular matrix, and chromatin sequestration in the susceptibility of uveal melanoma to herpes simplex virus type 1

“…It is notable that these nuclear changes occur later than 2 hours after virus inoculation and thus later than chromatin exposure reported in this study. HSV-1 and HSV-2 infection can induce chromatid and chromosome breaks and uncoiling of the centromeres of some chromosomes as early as 2-3 hours post infection (reviewed by Fortunato and Spector, 2003), however, global reversal of chromatin sequestration following HSV infection observed in our current study has not been reported.…”

Brain morphological changes associated with exposure to HSV1 in first-episode schizophrenia

“…63 HSV1 infection during the early brain development periods have been shown to cause chromosome damage that may show later cerebral and behavioral abnormalities. 64 Interestingly, chromosome breaks, pulverization and uncoiling of centromeres of chromosomes 1, 9 and 16, 65 with chromosome regions 1p32, 1q32 and 3p21 being the most susceptible 66 have been demonstrated. These observations were made on peripheral leukocytes, and human embryonic kidney and lung cells.…”

Human Cytomegalovirus Induces Drug Resistance and Alteration of Programmed Cell Death by Accumulation of ΔN-p73α

“…Thus, various proteins have been shown to accumulate in HCMV-infected cells (5,8). p73␣ and ⌬N-p73␣ isoforms are both sensitive to proteasome degradation (28,29).…”