Fig. 2 –

Repair Accident (RA) model. When temozolomide (TMZ) reacts with DNA it produces a variety of adducts among which the N-alkyl adducts, N7-mG and N3-mA, represent >80% of all alkylation events. Importantly, 8–9% of the lesions induced by TMZ include O⁶-mG. O-alkylation adducts are a hallmark of SN1 alkylating agents. The BER pathway acts at N-alkyl adducts, while the core MMR proteins recognize O⁶-mG:C base pairs. In TMZ treated DNA, initiation of MMR involves recognition by MutSα of the O⁶-mG:C base pair. MMR-mediated gap formation starts at a nick made by MutLα or at a nick produced by BER during repair of a nearby N-alkylation adduct. In contrast to MMR at the replication fork, lack of an instruction signal makes it equally likely that the initiating nick is in either strand. In any case, Exo1-mediated strand degradation or helicase unwinding proceeds towards the initiating O⁶-mG:C lesion. With an average MMR excision track length of several hundred bases, the accidental occurrence of another nicked BER intermediate in the opposite strand will give rise to a DSB. We suggest naming such a circumstance a “Repair Accident” [9].