Deoxyribonucleotide metabolism, mutagenesis and cancer

Mathews, Christopher K.

doi:10.1038/nrc3981

Cited by 154 publications

(187 citation statements)

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%

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Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

Rentoft

Lindell

Tran

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

101

151

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Even small variations in dNTP concentrations decrease DNA replication fidelity, and this observation prompted us to analyze genomic cancer data for mutations in enzymes involved in dNTP metabolism. We found that sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1), a deoxyribonucleoside triphosphate triphosphohydrolase that decreases dNTP pools, is frequently mutated in colon cancers, that these mutations negatively affect SAMHD1 activity, and that several SAMHD1 mutations are found in tumors with defective mismatch repair. We show that minor changes in dNTP pools in combination with inactivated mismatch repair dramatically increase mutation rates. Determination of dNTP pools in mouse embryos revealed that inactivation of one SAMHD1 allele is sufficient to elevate dNTP pools. These observations suggest that heterozygous cancer-associated SAMHD1 mutations increase mutation rates in cancer cells.

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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%

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

Rentoft

Lindell

Tran

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

101

151

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“…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%

p21 Restricts HIV-1 in Monocyte-Derived Dendritic Cells through the Reduction of Deoxynucleoside Triphosphate Biosynthesis and Regulation of SAMHD1 Antiviral Activity

Valle-Casuso

Allouch

David

et al. 2017

J Virol

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HIV-1 infection of noncycling cells, such as dendritic cells (DCs), is impaired due to limited availability of deoxynucleoside triphosphates (dNTPs), which are needed for HIV-1 reverse transcription. The levels of dNTPs are tightly regulated during the cell cycle and depend on the balance between dNTP biosynthesis and degradation. SAMHD1 potently blocks HIV-1 replication in DCs, although the underlying mechanism is still unclear. SAMHD1 has been reported to be able to degrade dNTPs and viral nucleic acids, which may both hamper HIV-1 reverse transcription. The relative contribution of these activities may differ in cycling and noncycling cells. Here, we show that inhibition of HIV-1 replication in monocyte-derived DCs (MDDCs) is associated with an increased expression of p21cip1/waf, a cell cycle regulator that is involved in the differentiation and maturation of DCs. Induction of p21 in MDDCs decreases the pool of dNTPs and increases the antiviral active isoform of SAMHD1. Although both processes are complementary in inhibiting HIV-1 replication, the antiviral activity of SAMHD1 in our primary cell model appears to be, at least partially, independent of its dNTPase activity. The reduction in the pool of dNTPs in MDDCs appears rather mostly due to a p21-mediated suppression of several enzymes involved in dNTP synthesis (i.e., RNR2, TYMS, and TK-1). These results are important to better understand the interplay between HIV-1 and DCs and may inform the design of new therapeutic approaches to decrease viral dissemination and improve immune responses against HIV-1.IMPORTANCE DCs play a key role in the induction of immune responses against HIV. However, HIV has evolved ways to exploit these cells, facilitating immune evasion and virus dissemination. We have found that the expression of p21, a cyclin-dependent kinase inhibitor involved in cell cycle regulation and monocyte differentiation and maturation, potentially can contribute to the inhibition of HIV-1 replication in monocyte-derived DCs through multiple mechanisms. p21 decreased the size of the intracellular dNTP pool. In parallel, p21 prevented SAMHD1 phosphorylation and promoted SAMHD1 dNTPase-independent antiviral activity. Thus, induction of p21 resulted in conditions that allowed the effective inhibition of HIV-1 replication through complementary mechanisms. Overall, p21 appears to be a key regulator of HIV infection in myeloid cells.

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“…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.…”

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confidence: 99%

Influence of DNA Lesions on Polymerase-Mediated DNA Replication at Single-Molecule Resolution

Gahlon

Romano

Rueda

2017

Chem. Res. Toxicol.

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Faithful replication of DNA is a critical aspect in maintaining genome integrity. DNA polymerases are responsible for replicating DNA, and high-fidelity polymerases do this rapidly and at low error rates. Upon exposure to exogenous or endogenous substances, DNA can become damaged and this can alter the speed and fidelity of a DNA polymerase. In this instance, DNA polymerases are confronted with an obstacle that can result in genomic instability during replication, for example, by nucleotide misinsertion or replication fork collapse. It is important to know how DNA polymerases respond to damaged DNA substrates to understand the mechanism of mutagenesis and chemical carcinogenesis. Single-molecule techniques have helped to improve our current understanding of DNA polymerase-mediated DNA replication, as they enable the dissection of mechanistic details that can otherwise be lost in ensemble-averaged experiments. These techniques have also been used to gain a deeper understanding of how single DNA polymerases behave at the site of the damage in a DNA substrate. In this review, we evaluate single-molecule studies that have examined the interaction between DNA polymerases and damaged sites on a DNA template.■ CONTENTS

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Deoxyribonucleotide metabolism, mutagenesis and cancer

Cited by 154 publications

References 140 publications

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

p21 Restricts HIV-1 in Monocyte-Derived Dendritic Cells through the Reduction of Deoxynucleoside Triphosphate Biosynthesis and Regulation of SAMHD1 Antiviral Activity

Influence of DNA Lesions on Polymerase-Mediated DNA Replication at Single-Molecule Resolution

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