Regulation of DNA Alkylation Damage Repair: Lessons and Therapeutic Opportunities

Alkylation chemotherapy is one of the most widely used systemic therapies for cancer. While somewhat effective, clinical responses and toxicities of these agents are highly variable. A major contributing factor for this variability is the numerous distinct lesions that are created upon alkylation damage. These adducts activate multiple repair pathways. There is mounting evidence that the individual pathways function cooperatively, suggesting that coordinated regulation of alkylation repair is critical to prevent toxicity. Furthermore, some alkylating agents produce adducts that overlap with newly discovered methylation marks, making it difficult to distinguish between bona fide damaged bases and so-called ‘epigenetic’ adducts. Here, we discuss new efforts aimed at deciphering the mechanisms that regulate these repair pathways, emphasizing their implications for cancer chemotherapy. Alkylation damage repair involves multiple partially redundant pathways, which include direct reversal by O6-methylguanine DNA methyltransferase (MGMT), the ALKB family of demethylases, and base excision repair (BER). Myriad regulatory mechanisms of these pathways exist. These include epigenetic control, post-translational modifications of repair proteins, and cellular metabolic status. Recent work has highlighted the importance of coordination within the individual alkylation repair pathways, as well as cooperation between them. Alkylation adducts repaired by these pathways overlap with newly discovered methylation marks with possible epigenetic functions, highlighting the importance of regulating these repair pathways. Understanding the molecular mechanisms of alkylation repair regulation will likely provide opportunities for improved cancer chemotherapy.