Mechanisms of MTH1 inhibition-induced DNA strand breaks: The slippery slope from the oxidized nucleotide pool to genotoxic damage

Unlike normal tissues, tumor cells possess a propensity for genomic instability, resulting from elevated oxidant levels produced by oncogenic signaling and aberrant cellular metabolism. Thus, targeting mechanisms that protect cancer cells from the tumor-inhibitory consequences of their redox imbalance and spontaneous DNA-damaging events is expected to have broad-spectrum efficacy and a high therapeutic index. One critical mechanism for tumor cell protection from oxidant stress is the hydrolysis of oxidized nucleotides. Human MutT homolog 1 (MTH1), the mammalian nudix (nucleoside diphosphate X) pyrophosphorylase (NUDT1), protects tumor cells from oxidative stress-induced genomic DNA damage by cleansing the nucleotide pool of oxidized purine nucleotides. Depletion or pharmacologic inhibition of MTH1 results in genomic DNA strand breaks in many cancer cells. However, the mechanisms underlying how oxidized nucleotides, thought mainly to be mutagenic rather than genotoxic, induce DNA strand breaks are largely unknown. Given the recent therapeutic interest in targeting MTH1, a better understanding of such mechanisms is crucial to its successful translation into the clinic and in identifying the molecular contexts under which its inhibition is likely to be beneficial. Here we provide a comprehensive perspective on MTH1 function and its importance in protecting genome integrity, in the context of tumor-associated oxidative stress and the mechanisms that likely lead to irreparable DNA strand breaks as a result of MTH1 inhibition.