J. Cell Sci. Suppl. 6, 333-353 (¡987) Printed in Great Britain © The Company of Biologists Limited 1987 333 THE ROLE OF 0 6- METHYLGUANINE IN HUMAN CELL KILLING, SISTER CHROMATID EXCHANGE INDUCTION AND MUTAGENESIS: A REVIEW RUFUS S. DAY, III Molecular Genetics and Carcinogenesis Program, Department of Medicine, Cross Cancer Institute, Edmonton, Alberta, Canada T6G 1Z2 MICHAEL A. BABICH Nucleic Acids Section, Laboratory of Molecular Carcinogenesis, DCE, NCI, NIH, Bethesda, Maryland 20892, USA DANIEL B. YAROSH Applied Genetics, Inc., 205 Buffalo Ave, Freeport, N Y 11520, USA a n d DOMINIC A. SCUDIERO Program Resources Incorporated, Frederick Cancer Research Facility, PO Box B, Frederick, M D 21701, USA SUMMARY 0 6- methylguanine (06mG) produced in DNA by such SN1 methylating agents as iV-methyl-A’- nitrososurea and iV- methyl- iV'- nitro- Af- nitrosoguanidine (MNNG) has been suggested by some to be the lesion that leads to certain biological endpoints in mammalian cells: cell killing, sister chromatid exchange (SCE) production, mutagenesis and cellular transformation. Other evidence is interpreted as inconsistent with this point of view. The finding of Karran & Williams (1985) that 0 6mG delivered to cells in culture resulted in the depletion of the activity of the protein responsible for repair of 0 6mG in DNA (06mG- DNA methyltransferase, 0 6MT) provided a tool for the assessment of the role of 0 6mG in producing biological endpoints. In this paper we review much of the literature on human cells pertinent to this question. In addition we present our survival data obtained using the depletion technique of Karran & Williams as well as data supporting a model invoking a mismatch and excision response to 0 6mG proposed by Sklar & Strauss (1980). Although data linking 0 6mG to causation are inconclusive, it is premature to conclude that 0 6mG is not a lesion lethal to certain cultured cells. INTRODUCTION The ideal system: one base change/one lethal hit It is important to know the identity of the DNA lesions that produce biological endpoints such as sister chromatid exchange (SCE) induction, mutation and loss of reproductive capacity, because this knowledge will lead to the experimental determination of the molecular mechanism by which these endpoints are caused. Identification of the initiating lesion is merely the first step. The fact that the production of about one pyrimidine dimer per genome correlated with the production of one ‘lethal hit’ in a population of uvrA recA Escherichia coli (Howard- Flanders & Boyce, 1966) demonstrated the possibility of assigning specific DNA lesions to the production of biological endpoints in genomes having of the order of