Simian Virus 40-induced Mutagenesis: Action of the Early Viral Region

Abstract

SUMMARYEarlier results have demonstrated a mutagenic activity of simian virus 40 (SV40) in mammalian cells. To analyse this ability further, the effect of SV40 DNA fragments, introduced into Chinese hamster cells, on the frequency of mutations at the hypoxanthine phosphoribosyltransferase locus and other loci was studied. It was found that the mutagenic effect (i) was substantially maintained when the viral genome had been replaced by a fragment comprising the T antigen-coding region and the early promoter--enhancer region, (ii) was strongly reduced or abolished when the promoter region including upstream sequences in this fragment had been replaced by the chicken lysozyme gene promoter or both enhancer elements were deleted, and (iii) was abolished in an SV40 replication origin-defective mutant in which the structure of the T antigen-binding site II was affected. It may be concluded that SV40-induced mutagenesis depends on the expression of the early region of the genome and on a function involved in specific binding of large T antigen to viral DNA. Since origindefective mutants of SV40 were reported as being able to transform cells, the functions of transformation and mutation do not seem to correlate.

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

“…Retention of viral sequences was observed in some SV40-induced rodent cell mutant clones [39] (a result which we could not find for a number of BKV-induced mutants tested so far in preliminary experiments). Concerning the mutational mechanism of SV40 activation of error-prone repair processes and/or mutator-like activity of large-T antigen has been discussed [40]. Further work to define the types of mutations that are induced by polyomavirus infection may provide information on the mechanism of mutagenesis.…”

“…It m a y be concluded (i) that the rearrangement which h a p p e n e d in B K V -I R has raised the viral capacity to m u t a t e rodent cells and (ii) that small-t protein activity is not necessarily required for polyomaviruses to be mutagenic. For mutagenicity testing of JC virus, owing to complications connected with preparing highly titered JCV [45] cells were infected with viral D N A as an alternative [40]. As shown in Fig.…”

“…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.…”

Evaluation of the mutagenic effects of SV40 in mouse, hamster, and mouse-human hybrid cells

“…Investigators have reported no mutagenic effect of SV40 in some experiments and 12-fold or greater increases in the frequency of mutants in other experiments. Conflicting results have been obtained regarding the role of T antigen in SV40-mediated mutagenesis (13,(15)(16).…”