Sanitation enzymes: Exquisite surveillance of the noncanonical nucleotide pool to safeguard the genetic blueprint

Reactive oxygen species (ROS) are common products of normal cellular metabolism, but their elevated levels can result in nucleotide modifications. These modified or noncanonical nucleotides often integrate into nascent DNA during replication, causing lesions that trigger DNA repair mechanisms such as the mismatch repair machinery and base excision repair. Four superfamilies of sanitization enzymes can effectively hydrolyze noncanonical nucleotides from the precursor pool and eliminate their unintended incorporation into DNA. Notably, we focus on the representative MTH1 NUDIX hydrolase, whose enzymatic activity is ostensibly nonessential under normal physiological conditions. Yet, the sanitization attributes of MTH1 are more prevalent when ROS levels are abnormally high in cancer cells, rendering MTH1 an interesting target for developing anticancer treatments. We discuss multiple MTH1 inhibitory strategies that have emerged in recent years, and the potential of NUDIX hydrolases as plausible targets for the development of anticancer therapeutics.

Automated summary

Reactive oxygen species (ROS) are common products of cellular metabolism and can cause nucleotide modifications. Noncanonical nucleotides integrated into DNA during replication can be hydrolyzed by sanitization enzymes. The MTH1 NUDIX hydrolase is a potential target for developing anticancer treatments due to its increased activity in cancer cells with high ROS levels. Multiple strategies for MTH1 inhibition have emerged, highlighting the potential of NUDIX hydrolases for anticancer therapeutics.