Balancing repair and tolerance of DNA damage caused by alkylating agents

Abstract

Chemotherapeutic alkylating agents induce a range of cytotoxic and mutagenic adducts onto DNA. Alkylating agent-induced damage to DNA is sensed and repaired by different cellular mechanisms, including direct repair by the AlkB homologue (ALKBH) family and O⁶-methylguanine-DNA methyltransferase (MGMT) proteins or by pathways such as base excision repair (BER), mismatch repair (MMR), homologous recombination, Fanconi anaemia and translesion DNA synthesis (TLS). Diverse cellular pathways collectively modulate alkylation sensitivity, and imbalances within or between these pathways can have deleterious consequences at the cellular and whole-animal levels. Developing agents to modulate DNA repair pathways is a promising strategy to increase the effectiveness of current chemotherapeutic alkylating agents. Investigation of DNA repair capacity in cancer patients may provide crucial information about which chemotherapeutic therapies to use, because differences can result in drastic variation in alkylation sensitivity.