Regulation of DNA Alkylation Damage Repair: Lessons and Therapeutic Opportunities

Abstract

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.

Keywords: AlkB; MGMT; alkylation chemotherapy; base excision repair.

Figure 1. Biochemical mechanisms of alkylation damage repair regulation relevant to tumor therapy

(A) MGMT gene silencing by DNA methylation leads to improved tumor responses to monomethylating agents such as TMZ. (B) Loss of mismatch repair leads to increased transition mutations, which may create higher rates of neoantigen expression upon alkylation damage. A combination of alkylation chemotherapy and immune checkpoint blockade may be effective. (C) Expression of mutant DNA Polβ may result in an imbalance in BER. In certain cases of imbalanced BER, inhibition of PARP or PARG may be a viable therapeutic. (D) Increased expression of ALKBH2/3 due to the OTUD4/USP7/USP9X deubiquitinase pathway may be countered using small molecule inhibitors against USP7 or USP9X. (E) IDH mutant tumors express the oncometabolite 2-hydroxyglutarate, which inhibits AlkB type demethylases. In these tumors the alkylating agent busulfan or chlorethylating alkylating agents may be more effective.

Figure 2. Potential mechanisms of alkylation damage-induced ‘epigenetic confusion’

(A) 1-meA is associated with 5’ UTRs of actively translated mRNAs. Induction of alkylation damage may hinder translation if 1-meA is present in the mRNA coding region. (B) Formation of 6meA from 1meA through Dimroth rearrangement. In the chromatin environment, residues such as lysine may promote nucleophilic attack of 1meA, leading to a ring-opened intermediate, which rearranges to form 6meA. As 6meA may have an epigenetic role in DNA, this conversion may lead to its inappropriate placement and function.