Effects of carcinogenic agents upon different mechanisms for intragenic recombination in mammalian cells

Abstract

A growing body of carcinogens are known to affect genetic recombination in mammalian cells and to thereby interfere with the process of carcinogenesis. In order to screen for recombinogenic effects of chemical and physical agents a variety of in vitro assay systems utilizing mammalian cells have been developed. However, the effects of potential carcinogens differ in these different systems. In order to investigate this phenomenon further, we have employed two different assay procedures, involving spontaneous duplication mutants in mammalian cells, which respond to homologous or non-homologous recombination. Four carcinogens were investigated, i.e. Aroclor 1221, benzene, methylmethanesulphonate (MMS) and thiourea, as were gamma- and UV-irradiation. With the exception of thiourea all of these factors resulted in elevated frequencies of homologous recombination. On the other hand, only UV-irradiation affected the rate of non-homologous recombination. These results indicate that substrate length and/or the recombination mechanism may influence the recombinogenic response of mammalian fibroblasts to carcinogenic factors. Thus, procedures for recombinogenic effects of carcinogens should consider the different pathways of recombination occurring in mammalian cells.

Genetic Interactions between BLM and DNA Ligase IV in Human Cells

“…However, abnormally increased levels of such lesions in cells treated with MMS or UV light would become a strong blocker of replication fork progression during S phase and generate abundant one-ended sister chromatids (50,51). HU treatment also arrests fork progression by nucleotide depletion, leading to stalled forks in the same manner as above (52).…”

Arsenic[III] and heavy metal ions induce intrachromosomal homologous recombination in thehprt gene of V79 Chinese hamster cells

“…This medium was supplemented with 6-thioguanine (5 g/mL) in order to reduce the frequency of spontaneous reversion prior to treatment Jenssen, 1992, 1994;Helleday et al, 1998b].…”

“…These duplication mutants revert spontaneously to a functional hprt gene via two different mechanisms for intrachromosomal recombination, i.e., homologous recombination in the case of the SPD8 cell line and nonhomologous recombination in the Sp5 cell line [Helleday et al, 1998a,b]. The reversion frequencies of both cell lines can be elevated in a dose-dependent manner by recombinogenic agents [Zhang and Jenssen, 1994;Helleday et al, 1998b]. In order to obtain further insight into the nature of the recombinations induced by the metal ions investigated, clones derived from cells heavily exposed to metals were selected, and the sequence of their hprt gene determined.…”

Polychlorinated Biphenyls and Polybrominated Biphenyls

“…Aroclor 1221 caused intrachromosomal recombination at the Hprt locus in a mutant Chinese hamster V79 cell line (Helleday et al, 1998), and in human lymphoblastoid cells (Aubrecht et al, 1995). Aroclor 1016 enhanced DNA-adduct formation in primary human lymphocytes (Borlak et al, 2003); no increase in the frequency of chromosomal aberration was seen in chicken embryos and ouabain-resistant colonies in Chinese hamster V79 cells treated with Aroclor 1242 (Blazak & Marcum, 1975;Hattula, 1985).…”