Virus-induced gene mutations of eukaryotic cells

Abstract

Most animal viruses studied so far induce chromosomal aberrations. In addition, adenoviruses, papovaviruses, and retroviruses are known to induce gene mutations like mutagenic bacteriophages. At least in one case studied retrovirus induced mutagenesis involves gene and/or scripton splitting analogous to the mutagenic mechanism of action of mutatorphage Mu and other movable DNA elements. On the contrary, several results obtained by independent means indicate that Simian virus 40, a papovavirus, does not act by splitting the affected gene but presumably by generation of base pair substitutions or of other minor DNA damages leading to amino acid substitutions. The mechanisms involved are still unknown. There a some hints, however, that these mechanisms might have some step(s) in common with processes leading to malignancy. In fact those viruses proved unequivocally so far to be capable of inducing gene mutations are oncogenic viruses.

Hepatitis B virus integration site in hepatocellular carcinoma at chromosome 17;18 translocation.

“…A related hit-andrun mechanism is probably responsible for herpes simplex virus transformation. All human herpesviruses induce chromosomal aberrations (19,33) and recent work has shown that the transforming sequences of herpes simplex virus types 1 and 2 and of cytomegalovirus contain DNA sequences with structural characteristics similar to insertion-sequence elements (34). Restriction enzymes that cut within these elements destroy the transformation activity, possibly by preventing their action as insertion sequences.…”

“…In the case of chemical hepatocarcinogenesis in the mouse and rat, agents that damage DNA stimulate the occurrence of HCC (15)(16)(17)(18). The ability of oncogenic viruses to damage DNA through integration and by increasing the mutation rate of cellular genes is probably an important factor in virusmediated multistage carcinogenesis (19). To investigate the possible role of HBV integrations in a general mechanism involving host DNA rearrangements, we have studied the structure of cellular DNA sequences at HBV integration sites.…”

Mutagenic activity of BKV and JCV in human and other mammalian cells

“…Such an outcome can be reasonably explained with variants of residual HPRT enzyme activity caused by mutations in different loci of the HPRT gene [37]. Earlier results on SV40-induced mutagenesis led to the conclusion of point mutations having occurred in the majority of TG r mutants, were compatible with the assumption of a structurally altered enzyme dihydrofolate reductase in antifolate drug resistant mutants, or were interpreted by base exchange mutations having led to Oua resistance [11,38]. But other types of mutations shown to cause these kinds of drug resistance too [20,32,43] might also be involved.…”

“…The combined action of both mutagens resulted in a mutant production in V79 cells much exceeding the sum of mutants produced by single treatments (Table 1). Therefore, in BKV-infected mammalian cells virus-induced mutations are detectable in dependence on the viral dose, the operative mutation expression time and possible synergistic effects elicited by combined action of the virus and another mutagen -findings that seem to be analogous to effects described earlier for the simian papovavirus SV40 [11]. [7,47] it seemed to be intersting to c o m p a r e the mutagenic effects o f wild-type virus and B K V -I R , a virus variant isolated from a h u m a n t u m o r and bearing b o t h an insertion and a deletion in the early region o f the genome [27].…”

“…This idea was substantiated by the finding that some viruses of the papova, adeno, and herpes groups as well as retroviruses are able to mutate cells cultured in vitro [5,17,28,34, for further review see 11]. The oncogenic polyomavirus SV40 was shown to M. Theite and Gabriete Grabowski induce resistance mutants affecting different cellular genes, a process which depends on the expression of the early region of the viral genome as well as, most likely, on a function involved in specific binding of large T antigen to viral DNA; the virus acts synergistically in combination with different chemical and physical mutagens; and, though the mutagenic activity is essentially detectable at early stages of viral infection, clones of SV40-induced specific-locus mutants were found to show increased spontaneous mutability of other markers [ 11,39,40]. In view of these findings it should be borne in mind that genotoxic effects might be caused by two related polyomaviruses, BKV and JCV, whose natural host in man.…”