The relationship between O6-alkylguanine alkyltransferase activity and sensitivity to alkylation-induced sister chromatid exchanges in human lymphoblastoid cell lines.

Abstract

We investigated the relationship between the ability to repair the O6-alkylguanine lesions and sister chromatid exchange (SCE) induction. Six human lymphoblastoid cell lines, with O6-alkylguanine alkyltransferase (AGT) activities ranging from 0 to 13.2 fmol/micrograms DNA, were tested for their sensitivity to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-, methyl methanesulfonate (MMS)- and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)-induced SCEs. L33, a long established lymphoblastoid cell line with no AGT activity, was sensitive to all three alkylating agents. In the other more recently established Epstein-Barr virus transformed cell lines, no correlation between AGT activity (ranging from 2.4 to 13.2 fmol/micrograms DNA) and sensitivity to MMS or MNNG was noted. In fact, of these five cell lines, the cell line with the highest AGT activity, line 852A, was the most sensitive to MNNG-induced SCEs. While cell lines differed in overall alkylation by MNNG, no relationship between overall akylation and sensitivity to MNNG-induced SCE formation was noted. In contrast to the results with the monofunctional alkylating agents, there was a correlation between AGT activity and BCNU-sensitivity to SCE induction. Cell lines with low AGT activities were more sensitive to the bifunctional alkylating agent than cells with higher activities. Therefore, while DNA interstrand cross-links produced by BCNU exposure probably underlie SCE induction by this agent, the lesions and processes that lead to SCE induction after exposure to monofunctional alkylating agents remain unclear.