TRANSGENIC SYSTEMS IN STUDIES ON GENOTOXICITY OF ALKYLATING-AGENTS - CRITICAL LESIONS, THRESHOLDS AND DEFENSE-MECHANISMS

Transgenic systems, both cell lines and mice with gain or loss of func tion, are being used in order to modulate the expression of DNA repair proteins, thus allowing to assess their contribution to the defense a gainst genotoxic mutagens and carcinogens. In this review, questions h ave been addressed concerning the use of transgenic systems in elucida ting critical primary DNA lesions, their conversion into genotoxic end points, low-dose effects, and the relative contribution of individual cellular functions in defense. It has been shown that the repair prote in alkyltransferase (MGMT) is decisive for protection against methylat ing and chloroethylating compounds. Protection pertains also to tumor formation, as revealed by the response of MGMT transgenic and knockout mice. Overexpression of genes involved in base excision repair (N-met hyl-purine-DNA glycosylase, apurinic endonuclease, DNA polymerase beta ) is in most cases not beneficial in increasing the protection level, whereas their down-modulation or inactivation increases cellular sensi tivity. This indicates that non-repaired base N-alkylation lesions and /or repair intermediates possess genotoxic potential. Modulation of mi smatch repair and poly(ADP)ribosyl transferase has also been shown to affect the cellular response to alkylating agents. Furthermore, the ro le of Fos, Jun and p53 in cellular defense against alkylating mutagens is discussed. (C) 1998 Elsevier Science B.V. All rights reserved.