A Critical Balance: dNTPs and the Maintenance of Genome Stability

Abstract

A crucial factor in maintaining genome stability is establishing deoxynucleoside triphosphate (dNTP) levels within a range that is optimal for chromosomal replication. Since DNA replication is relevant to a wide range of other chromosomal activities, these may all be directly or indirectly affected when dNTP concentrations deviate from a physiologically normal range. The importance of understanding these consequences is relevant to genetic disorders that disturb dNTP levels, and strategies that inhibit dNTP synthesis in cancer chemotherapy and for treatment of other disorders. We review here how abnormal dNTP levels affect DNA replication and discuss the consequences for genome stability.

Regulation of Nucleotide Metabolism and Germline Proliferation in Response to Nucleotide Imbalance and Genotoxic Stresses by EndoU Nuclease

“…Nucleotides (NTs) are building blocks for DNAs and RNAs and indispensable for many important cellular processes, such as DNA damage response and energy production. Both the absolute levels and the balance between different NTs are critical for genome stability (Pai and Kearsey, 2017). Therefore, to survive the fluctuation in NT levels due to changes in diet or internal NT metabolic conditions, animals are expected to have evolved cellular mechanisms that sense and respond to NT level changes.…”

“…Therefore, to survive the fluctuation in NT levels due to changes in diet or internal NT metabolic conditions, animals are expected to have evolved cellular mechanisms that sense and respond to NT level changes. Although there have been extensive studies regarding the impact of nucleotide imbalance on cell-cycle progression, DNA replication, and genome stability mainly using cultured cells or yeast (Pai and Kearsey, 2017), the mechanisms that regulate developmental and metabolic events in animal models in response to NT changes are underexplored.…”

Fast and sensitive HPLC–MS/MS method for direct quantification of intracellular deoxyribonucleoside triphosphates from tissue and cells

“…dNTP pools are tightly controlled and an imbalance of dNTPs is observed in a variety of disease conditions such as cancer and mitochondrial diseases[1,2]. Both imbalanced dNTP pools as well as irregularly large amounts of all dNTPs have been shown to be associated with increased errors in nucleotide selectivity combined with inefficient proofreading during DNA replication and eventual oncogenesis, likely attributed to this buildup of mutations[3,4].…”

“…Both imbalanced dNTP pools as well as irregularly large amounts of all dNTPs have been shown to be associated with increased errors in nucleotide selectivity combined with inefficient proofreading during DNA replication and eventual oncogenesis, likely attributed to this buildup of mutations[3,4]. During the cell cycle, dNTP pools are augmented for DNA synthesis and are generally elevated during proliferation [1,5]. However, in non-dividing cells, the total dNTP pool is about 1–10 pmol/million cells and less than 1 pmol in the mitochondria[6].…”

SAMHD1: Recurring roles in cell cycle, viral restriction, cancer, and innate immunity

“…dNTPs differ by only a single atom from ribonucleotide triphosphates (NTPs) yet are maintained at 10–1000 times lower concentration (1). A balanced supply of each of the four canonical dNTPs maintained at proper concentrations is required for accurate genomic and mitochondrial DNA synthesis and repair (2–5). As such, nucleotide metabolism is precisely regulated within cells.…”