Balancing repair and tolerance of DNA damage caused by alkylating agents

Abstract

Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER) and mismatch repair (MMR), respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for a favourable response of an organism to alkylating agents. Furthermore, the response of an individual to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity.

Figures

Figure 1. Sites of alkylation on DNA bases

Figure 2. DNA lesions induced by monofunctional and bifunctional chemotherapeutic alkylating agents

Figure 3. Mammalian repair and tolerance mechanisms for DNA alkylated bases

Figure 4. DNA repair mechanisms for alkylated bases

Figure 5. Cellular processing and repair of 3meA lesions in DNA

Figure 6. Cellular processing and repair ofO6meG lesions in DNA