**7. Alkylation Damage Repair: Dual Consequences**

Alkylating antitumor agents produce many damaged bases, including *O*<sup>6</sup> -alkylguanine repaired by *O*<sup>6</sup> -methylguanine–DNA methyltransferase (MGMT), and ring-alkylated purines repaired predominantly by BER [16,208]. Unlike other DNA glycosylases, which impart resistance to DNA-damaging agents to cells, *N*-methylpurine-DNA glycosylase (MPG, alias alkyladenine-DNA glycosylase (AAG), and alkylpurine-DNA *N*-glycosylase, APNG) may increase the cytotoxicity of alkylating antitumor agents, removing alkylated bases from DNA to form AP sites, which are more dangerous for the cell [208–214]. A similar sensitization mechanism is also characteristic of UNG, TDG, and MBD4 DNA glycosylases when they repair C5-halogenated uracil derivatives [215–218]. On the other hand, inhibition of MPG in carcinoma cells sensitizes them to alkylating agents [219], and *Mpg*−/<sup>−</sup> murine cells are hypersensitive to 1,3-bis(2-chloroethyl)-1-nitrosourea and mitomycin C (but not to alkylating nitrogen mustards) [220]. An integrative model of temozolomide-induced DNA damage and DNA repair by MGMT and MPG in glioblastoma predicts that inhibition of both enzymes is the most successful sensitization strategy [221]. For temozolomide-resistant forms of glioblastoma, the combination of inhibition of BER enzymes and PARP-dependent signaling is effective [212,222]. In addition to the detoxification of anticancer drug adducts, MPG and OGG1 have been reported to hydrolyze a human cytomegalovirus replication inhibitor, 2-bromo-5,6-dichloro-1-(β-d-ribofuranosyl)benzimidazole, opening the possibility of antiviral action of drug combinations including DNA glycosylase inhibitors [223]. Bacterial *alkA* mutants are hypersensitive to methyl methanesulfonate [224,225]; however, alkylating agents are not among clinically used antibacterial drugs, so this vulnerability is hard to exploit.

Alkylbase-removing DNA glycosylases are the least explored group in terms of specific inhibitors. N3-substituted adenine derivatives are competitive inhibitors of bacterial Tag and mammalian MPG [226–230]. Based on this observation, a series of structural analogs has been computationally designed to inhibit TagA from *Leptospira interrogans*, the infectious agent of leptospirosis, although no experimental evidence was provided for their activity against the enzyme or the pathogen [231]. A natural flavonol, morin, inhibits MPG [78] (Table 2).
