O6-methylguanine-DNA methyltransferase (MGMT): can function explain a suicidal mechanism?

Abstract

Why does O6-methylguanine-DNA methyltransferase (MGMT), an indispensable DNA repair enzyme, have a mechanism which seems to run counter to its importance? This enzyme is key to the removal of detrimental alkyl adducts from guanine bases. Although the mechanism is well known, an unusual feature surrounds its mode of action, which is its so-called suicidal endpoint. In addition, induction of MGMT is highly variable and its kinetics is atypical. These features raise some questions on the seemingly paradoxical mechanism. In this manuscript we point out that, although there is ample literature regarding the “how” of the MGMT enzyme, we found a lack of information on “why” this specific mechanism is in place. We then ask whether we know all there is to know about MGMT, or if perhaps there is a further as yet unknown function for MGMT, or if the suicidal mechanism may play some kind of protective role in the cell.