Inhibition of DNA synthesis facilitates expansion of low‐complexity repeats

Kuzminov, Andrei

doi:10.1002/bies.201200128

Cited by 14 publications

(12 citation statements)

References 88 publications

(98 reference statements)

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“…The other study, primarily a speculation at this stage, pertains to dNTP metabolism and the generation of trinucleotide repeats (73). It is generally accepted that repeats are generated by template‐primer slippage during DNA replication.…”

Section: Telomeres and Microsatellite Repeatsmentioning

confidence: 99%

“…It is generally accepted that repeats are generated by template‐primer slippage during DNA replication. Kuzminov (73) speculated, for example, that replication of a C‐rich template could cause localized depletion of dGTP in the vicinity of a replication fork, a condition that could retard replication, favoring slippage. The question here, of course, is the rate at which locally depleted dNTP pools can be refilled by inward diffusion to replication sites.…”

Section: Telomeres and Microsatellite Repeatsmentioning

confidence: 99%

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Deoxyribonucleotides as genetic and metabolic regulators

Mathews

2014

FASEB j.

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For >35 yr, we have known that the accuracy of DNA replication is controlled in large part by the relative concentrations of the 4 canonical deoxyribonucleoside 5'-triphosphates (dNTPs) at the replisome. Since this field was last reviewed, ∼8 yr ago, there has been increased understanding of the mutagenic pathways as they occur in living cells. At the same time, aspects of deoxyribonucleotide metabolism have been shown to be critically involved in processes as diverse as cell cycle control, protooncogene expression, cellular defense against HIV infection, replication rate control, telomere length control, and mitochondrial function. Evidence supports a relationship between dNTP pools and microsatellite repeat instability. Relationships between dNTP synthesis and breakdown in controlling steady-state pools have become better defined. In addition, new experimental approaches have allowed definitive analysis of mutational pathways induced by dNTP pool abnormalities, both in Escherichia coli and in yeast. Finally, ribonucleoside triphosphate (rNTP) pools have been shown to be critical determinants of DNA replication fidelity. These developments are discussed in this review article.

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Section: Telomeres and Microsatellite Repeatsmentioning

confidence: 99%

Section: Telomeres and Microsatellite Repeatsmentioning

confidence: 99%

Deoxyribonucleotides as genetic and metabolic regulators

Mathews

2014

FASEB j.

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“…In contrast, the new model presented in the current issue of BioEssays proposes that polymerase slowing and nascent strand hairpins are not direct effects of the repeat on the polymerase; rather they are indirect consequences of local nucleotide depletion, which results from a local stoichiometric imbalance in nucleotide incorporation into the nas-cent DNA (repeat sequences manifest such imbalanced stoichiometries) [6]. The hypothesis predicts that nucleotide diffusion through the cell should be slower than the rate of precursor consumption at an individual replication fork.…”

mentioning

confidence: 99%

Hypothesis: Local dNTP depletion as the cause of microsatellite repeat instability during replication (Comment on DOI 10.1002/bies.201200128)

Leffak¹

2013

BioEssays

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“…The insertion mutations that we observed on leading strands in HEK293 cells have an extra adenine at the EcoRI site: G(HX)ATTC→GAAATTC. +1 frameshift mutations may be preferential to DNA fork collapse, or large scale deletions as we observed on lagging strand in HEK293 cells, and in HCT116 leading and lagging strands [45]. Further analysis on Y-family DNA polymerases and Hx by-pass will need to be performed on leading and lagging strands to understand these intricate mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Mutagenic potential of hypoxanthine in live human cells

Devito

Woodrick

Song

et al. 2017

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Hypoxanthine (Hx) is a major DNA lesion generated by deamination of adenine during chronic inflammatory conditions, which is an underlying cause of various diseases including cancer of colon, liver, pancreas, bladder and stomach. There is evidence that deamination of DNA bases induces mutations, but no study has directly linked Hx accumulation to mutagenesis and strand-specific mutations yet in human cells. Using a site-specific mutagenesis approach, we report the first direct evidence of mutation potential and pattern of Hx in live human cells. We investigated Hx-induced mutations in human nonmalignant HEK293 and cancer HCT116 cell lines and found that Hx is mutagenic in both HEK293 and HCT116 cell lines. There is a strand bias for Hx-mediated mutations in both the cell lines; the Hx in lagging strand is more mutagenic than in leading strand. There is also some difference in cell types regarding the strand bias for mutation types; HEK293 cells showed largely deletion (>80%) mutations in both leading and lagging strand and the rest were insertions and A:T→G:C transition mutations in leading and lagging strands, respectively, whereas in HCT116 cells we observed 60% A:T→G:C transition mutations in the leading strand and 100% deletions in the lagging strand. Overall, Hx is a highly mutagenic lesion capable of generating A:T→G:C transitions and large deletions with a significant variation in leading and lagging strands in human cells. In recent meta-analysis study A→G (T→C) mutations were found to be a prominent signature in a variety of cancers, including a majority types that are induced by inflammation. The deletions are known to be a major cause of copy-number variations or CNVs, which is a major underlying cause of many human diseases including mental illness, developmental disorders and cancer. Thus, Hx, a major DNA lesion induced by different deamination mechanisms, has potential to initiate inflammation-driven carcinogenesis in addition to various human pathophysiological consequences.

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Inhibition of DNA synthesis facilitates expansion of low‐complexity repeats

Cited by 14 publications

References 88 publications

Deoxyribonucleotides as genetic and metabolic regulators

Deoxyribonucleotides as genetic and metabolic regulators

Hypothesis: Local dNTP depletion as the cause of microsatellite repeat instability during replication (Comment on DOI 10.1002/bies.201200128)

Mutagenic potential of hypoxanthine in live human cells

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