Deoxyribonucleotide Triphosphate Metabolism in Cancer and Metabolic Disease

Abstract

The maintenance of a healthy deoxyribonucleotide triphosphate (dNTP) pool is critical for the proper replication and repair of both nuclear and mitochondrial DNA. Temporal, spatial, and ratio imbalances of the four dNTPs have been shown to have a mutagenic and cytotoxic effect. It is, therefore, essential for cell homeostasis to maintain the balance between the processes of dNTP biosynthesis and degradation. Multiple oncogenic signaling pathways, such as c-Myc, p53, and mTORC1 feed into dNTP metabolism, and there is a clear role for dNTP imbalances in cancer initiation and progression. Additionally, multiple chemotherapeutics target these pathways to inhibit nucleotide synthesis. Less is understood about the role for dNTP levels in metabolic disorders and syndromes and whether alterations in dNTP levels change cancer incidence in these patients. For instance, while deficiencies in some metabolic pathways known to play a role in nucleotide synthesis are pro-tumorigenic (e.g., p53 mutations), others confer an advantage against the onset of cancer (G6PD). More recent evidence indicates that there are changes in nucleotide metabolism in diabetes, obesity, and insulin resistance; however, whether these changes play a mechanistic role is unclear. In this review, we will address the complex network of metabolic pathways, whereby cells can fuel dNTP biosynthesis and catabolism in cancer, and we will discuss the potential role for this pathway in metabolic disease.

Metabolic characterization of colorectal cancer cells harbouring different KRAS mutations in codon 12, 13, 61 and 146 using human SW48 isogenic cell lines

“…Nucleotide pool imbalance has been proposed to be associated with enhanced mutagenesis and genomic instability, which promotes cancer (Kohnken et al 2015;Papadopoulou et al 2015). Deregulation of nucleotide metabolism is associated with a wide range of pathological conditions including cancer (Buj and Aird 2018;Kohnken et al 2015). In the present study, the significant increase of nucleosides (inosine, uridine) together with decrease of nucleotides (AMP, UMP) in the KRAS mutants could reflect rapid nucleotide turnover and salvage pathway activity of nucleic acid metabolism.…”

A sensitive assay for dNTPs based on long synthetic oligonucleotides, EvaGreen dye, and inhibitor-resistant high-fidelity DNA polymerase

“…Only handful of studies have addressed the topic of tissue dNTP levels in health and disease (6,(17)(18)(19). As nucleotide metabolism is more and more studied in the field of cancer biology and in relation to metabolic diseases such as mitochondrial disorders (19,24) the availability of an easily applicable dNTP assay for use in the general laboratory is of the utmost importance. The values represent mean ± SD.…”

Targeting IDH1 as a pro-senescent therapy in high-grade serous ovarian cancer

“…Tumor cells are characterized by metabolic reprogramming in order to maintain uncontrolled cell proliferation and growth (20). Tumors specifically reprogram metabolic pathways to allow for the increased need for biomass, such as nucleotides, lipids, and other macromolecules (21,22). This metabolic reprogramming is increasingly thought to modulate epigenetic marks, including histone and DNA methylation and histone acetylation (23).…”