DNA-processing enzymes (via 6-thioguanosine nucleotide incorporation)

DNA-processing enzymes targeted via 6-thioguanosine nucleotide incorporation represent a critical class of targets for thiopurine-based chemotherapy and immunosuppression. Thiopurine prodrugs, such as 6-thioguanine and 6-mercaptopurine, are intracellularly converted into 6-thioguanine nucleotides (6-TGNs) that are incorporated into the DNA of replicating cells (Karran & Attard, 2008). This incorporation disrupts the function of several key enzymes, most notably DNA methyltransferase 1 (DNMT1), which becomes irreversibly trapped on the DNA and subsequently degraded, leading to global DNA hypomethylation (Hoshino et al., 2012). Furthermore, the presence of 6-thioguanine in DNA is recognized by the mismatch repair (MMR) system, which initiates a signaling cascade leading to cell cycle arrest and apoptosis (Sahasranaman et al., 2008). The incorporation also affects DNA polymerases and ligases, potentially causing replication stress and genomic instability (Liu et al., 2014). This multi-faceted targeting of DNA-processing machinery is the basis for the clinical efficacy of thiopurines in treating acute leukemias and chronic inflammatory diseases like Crohn's disease and ulcerative colitis.

Other names

Thiopurine targets6-thioguanine-modified DNA targetsDNMT1 (as a thiopurine target)DNA mismatch repair-dependent targets6-TG-DNA adduct targets

Thiopurine drugs are metabolized into 6-thioguanine nucleotides (6-TGNs), which are incorporated into DNA in place of guanine. This modification interferes with the activity of various DNA-processing enzymes, such as DNA methyltransferase 1 (DNMT1), which becomes irreversibly trapped and degraded, and DNA polymerases, which may stall. The presence of 6-thioguanine in DNA also triggers the mismatch repair (MMR) system, leading to DNA strand breaks and apoptosis (Karran & Attard, 2008; Hoshino et al., 2012).