2015
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Abstract: Cancer was recognized as a genetic disease at least four decades ago, with the realization that the spontaneous mutation rate must increase early in tumorigenesis to account for the many mutations in tumour cells compared with their progenitor pre-malignant cells. Abnormalities in the deoxyribonucleotide pool have long been recognized as determinants of DNA replication fidelity, and hence may contribute to mutagenic processes that are involved in carcinogenesis. In addition, many anticancer agents antagonize d… Show more

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Cited by 133 publications
(135 citation statements)
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References 140 publications
(135 reference statements)
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“…This cell line lacks functional MMR due to a homozygous mutation of MLH1 (49), and it is commonly used for the analysis of mutation rates under different conditions (50)(51)(52). To alter intracellular dNTP pools in this cell line, we supplemented the cell culture medium with deoxyribonucleosides, which are stepwise phosphorylated by deoxynucleoside (dN) kinases and deoxyribonucleotide kinases into dNTPs (20). Addition of one deoxyribonucleoside at high concentrations results in a dramatic increase in one or several dNTPs and a depletion of one or several other dNTPs because of the allosteric regulation of RNR.…”
Section: Small Alteration Of Dntp Pools Dramatically Increases Mutatimentioning
confidence: 99%
See 1 more Smart Citation
“…This cell line lacks functional MMR due to a homozygous mutation of MLH1 (49), and it is commonly used for the analysis of mutation rates under different conditions (50)(51)(52). To alter intracellular dNTP pools in this cell line, we supplemented the cell culture medium with deoxyribonucleosides, which are stepwise phosphorylated by deoxynucleoside (dN) kinases and deoxyribonucleotide kinases into dNTPs (20). Addition of one deoxyribonucleoside at high concentrations results in a dramatic increase in one or several dNTPs and a depletion of one or several other dNTPs because of the allosteric regulation of RNR.…”
Section: Small Alteration Of Dntp Pools Dramatically Increases Mutatimentioning
confidence: 99%
“…The absolute and relative concentrations of dNTPs are controlled by several dozen proteins (20), and mutations or a change in abundance in any of these could in principle result in a distortion of the dNTP pool. Ribonucleotide reductase (RNR), dCMP deaminase, dUTPase, dTMP synthase, dTMP kinase, and NDP kinases control dNTP biosynthesis.…”
mentioning
confidence: 99%
“…Thus, the suppression of one of the enzymes involved in dNTP synthesis, whose expression is regulated by p21, appeared sufficient to block HIV-1 infection in myeloid cells. Because equilibrium among nucleotide levels is critical for cell survival and function (27), it is likely that changes in the level of one dNTP would lead to changes in that of the others. For instance, dTTP mediates allosteric regulation of RNR, and variations in dTTP levels may affect de novo synthesis of the other dNTPs (46,51).…”
Section: Discussionmentioning
confidence: 99%
“…The cellular dNTP pool is a critical limiting factor for HIV-1 replication (25,26) that is sustained by various cellular pathways (27): the salvage pathway recovers nucleotide intermediates from extracellular media and intracellular DNA degradation, and the de novo pathway synthetizes new dNTP molecules. The expression of the cellular factors involved in both pathways is strongly regulated by the cell cycle (28,29).…”
mentioning
confidence: 99%
“…6 Nucleotides can become damaged prior to being incorporated during replication. 7,8 In the event of a misinsertion, high-fidelity DNA Pols have an exonuclease domain or an associated subunit that can perform proofreading where an incorrect nucleotide is removed from the 3′ end of DNA, thereby increasing replication fidelity. 4,9 1.2.…”
mentioning
confidence: 99%