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

Abstract

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) pyrophosphatase (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.

Oxidative Damage in Sporadic Colorectal Cancer: Molecular Mapping of Base Excision Repair Glycosylases in Colorectal Cancer Patients

“…MTH1 preserves genomic integrity by preventing the incorporation of mutagenic purines into nuclear and/or mitochondrial DNA [63]. Depletion or inhibition of MTH1 also results in DNA strand breaks [64]. Additionally, MTH1 helps to protect telomeres, the essential structures at the end of chromosomes, from their oxidation and shortening and prevents the induction of genomic instability [65].…”

NUDT1-Knockdown Inhibits Proliferation, Invasion and Migration of CAL27

“…The expression level of NUDT1 is higher than the adjacent normal tissues in the oncogenic KRAS-driven cancers such as pancreatic and lung cancer [19]. The main protein production of NUDT1 is MTH1 protein, which expressed in cytoplasm and could hydrolyze the 8-oxo-dGTP into 8-oxo-dGMP or pyrophosphate [12,20]. Therefore, the gene mutation caused by 8-oxo-dGTP was inhibited by overexpressed NUDT1 and the cancer cell apoptosis could not be activated [21].…”

Purine-Metabolising Enzymes and Apoptosis in Cancer

“…It is mostly present in cytosol and, in lesser amounts, in mitochondria and in nuclei. Higher expression levels of the enzyme were found in thymus, testis, embryo, proliferating blood lymphocytes [193], and in cancer cells when compared with normal ones [194]. Its enzymatic activity, together with its cellular distribution and the overexpression in cancers, lead to hypothesise for MTH1 a possible role in the sanitization of nucleotide pools both for nuclear and mitochondrial DNA/RNA replication and transcription processes, preventing the misincorporation of oxidised nucleotides into nucleic acids (Figure 6, Panel 1).…”

“…A small increase in ROS levels promotes proliferation and cancer cell survival [196,197], whereas large amounts of ROS inhibit proliferation [198] and promote senescence [199,200] and apoptosis in several cancer models [200,201,202,203]. While it is widely accepted that MTH1 is dispensable in healthy cells [194], the role of the enzyme in removing oxidised dNTP in cancer cells, thus promoting their survival, and the consequent possibility to use this enzyme as a chemotherapeutic target, is controversial. These discordances, arising probably from the use in the different reports of different experimental conditions (inhibitors, siRNA, shRNA, or CRISPR technique) and models (cell cultures, xenograft, etc.…”