Targeting the DNA damage response and repair in cancer through nucleotide metabolism

• Published in: Molecular oncology Vol. 16; no. 21; pp. 3792 - 3810
• Main Authors: Helleday, Thomas, Rudd, Sean G.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.11.2022; John Wiley and Sons Inc; Wiley
• Subjects: Antimetabolites; Cancer; Cell cycle; Chemotherapy; Dehydrogenases; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA Damage; DNA damage response; DNA Repair; dNTP metabolism; E coli; Enzymes; Genetic aspects; Genomes; Humans; Laboratories; Leukemia; Lymphocytes; Mammals; Medicin och hälsovetenskap; Metabolic pathways; Metabolism; MTH1; MTHFD2; Mutation; Neoplasms - pathology; Nucleotides - metabolism; Oxidative stress; Physiological aspects; Proteins; Review; Reviews; Ribonucleotide reductase; SAMHD1; Senescence; cancer; MTH1; SAMHD1; DNA damage response; MTHFD2; dNTP metabolism
• ISSN: 1574-7891; 1878-0261; 1878-0261
• DOI: 10.1002/1878-0261.13227

The exploitation of the DNA damage response and DNA repair proficiency of cancer cells is an important anticancer strategy. The replication and repair of DNA are dependent upon the supply of deoxynucleoside triphosphate (dNTP) building blocks, which are produced and maintained by nucleotide metabolic pathways. Enzymes within these pathways can be promising targets to selectively induce toxic DNA lesions in cancer cells. These same pathways also activate antimetabolites, an important group of chemotherapies that disrupt both nucleotide and DNA metabolism to induce DNA damage in cancer cells. Thus, dNTP metabolic enzymes can also be targeted to refine the use of these chemotherapeutics, many of which remain standard of care in common cancers. In this review article, we will discuss both these approaches exemplified by the enzymes MTH1, MTHFD2 and SAMHD1. © 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. The exploitation of the DNA damage response and DNA repair proficiency of cancer cells is an important anticancer strategy. The replication and repair of the DNA molecule are dependent upon the supply of deoxynucleoside triphosphate (dNTP) building blocks, which are produced and maintained by nucleotide metabolic pathways. Here, we will discuss how targeting these pathways can be a promising anticancer strategy.