A Critical Balance: dNTPs and the Maintenance of Genome Stability

Genes, Journal Year: 2017, Volume and Issue: 8(2), P. 57 - 57

Published: Jan. 31, 2017

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

Language: Английский

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Fetuin-A: a novel link between obesity and related complications

International Journal of Obesity, Journal Year: 2014, Volume and Issue: 39(5), P. 734 - 741

Published: Dec. 3, 2014

Language: Английский

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The Yeast Cyclin-Dependent Kinase Routes Carbon Fluxes to Fuel Cell Cycle Progression

Molecular Cell, Journal Year: 2016, Volume and Issue: 62(4), P. 532 - 545

Published: May 1, 2016

Language: Английский

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The Origin and Evolution of Ribonucleotide Reduction

Life, Journal Year: 2015, Volume and Issue: 5(1), P. 604 - 636

Published: Feb. 27, 2015

Ribonucleotide reduction is the only pathway for de novo synthesis of deoxyribonucleotides in extant organisms. This chemically demanding reaction, which proceeds via a carbon-centered free radical, catalyzed by ribonucleotide reductase (RNR). The mechanism has been deemed unlikely to be ribozyme, creating an enigma regarding how building blocks DNA were synthesized at transition from RNA- DNA-encoded genomes. While it entirely possible that different was later replaced with modern mechanism, here we explore evolutionary and biochemical limits origin RNA + protein world suggest model prototypical (protoRNR). From protoRNR evolved ancestor RNRs, urRNR, diversified into three classes. Since initial radical generation differs between classes, difficult establish generated urRNR. Here similar B12-dependent class II RNRs.

Language: Английский

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Genome-wide analysis of the specificity and mechanisms of replication infidelity driven by imbalanced dNTP pools

Nucleic Acids Research, Journal Year: 2015, Volume and Issue: 44(4), P. 1669 - 1680

Published: Nov. 24, 2015

The absolute and relative concentrations of the four dNTPs are key determinants DNA replication fidelity, yet consequences altered dNTP pools on fidelity have not previously been investigated a genome-wide scale. Here, we use deep sequencing to determine types, rates locations uncorrected errors that accumulate in nuclear genome mismatch repair-deficient diploid yeast strain with elevated dCTP dTTP concentrations. These imbalanced promote specific sequence motifs suggesting increased misinsertion extension at expense proofreading. Interestingly, substitution similar for leading lagging strand replication, but higher regions replicated late S phase. Remarkably, rate single base deletions is preferentially coding sequences short rather than long mononucleotides runs. Based motifs, propose two distinct mechanisms generating vivo. Collectively, results indicate increase formation decrease error correction across genome, most strongly increases mutation replicating sequences.

Language: Английский

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Increased and Imbalanced dNTP Pools Symmetrically Promote Both Leading and Lagging Strand Replication Infidelity

PLoS Genetics, Journal Year: 2014, Volume and Issue: 10(12), P. e1004846 - e1004846

Published: Dec. 4, 2014

The fidelity of DNA replication requires an appropriate balance dNTPs, yet the nascent leading and lagging strands nuclear genome are primarily synthesized by replicases that differ in subunit composition, protein partnerships biochemical properties, including fidelity. These facts pose question whether imbalanced dNTP pools differentially influence strand Here we test this possibility examining strand-specific infidelity driven a mutation yeast ribonucleotide reductase, rnr1-Y285A, leads to elevated dTTP dCTP concentrations. results for CAN1 mutational reporter gene present opposite orientations reveal rates, surprisingly even sequence contexts, errors remarkably similar synthesis. Moreover, while many mismatches pool imbalance efficiently corrected mismatch repair, others repaired less efficiently, especially those contexts suggesting reduced proofreading due increased extension high Thus two at risk mutations resulting from imbalance, is not completely suppressed when both major error correction mechanisms genetically intact.

Language: Английский

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The mutation spectrum in genomic late replication domains shapes mammalian GC content

Nucleic Acids Research, Journal Year: 2016, Volume and Issue: 44(9), P. 4222 - 4232

Published: April 16, 2016

Genome sequence compositions and epigenetic organizations are correlated extensively across multiple length scales. Replication dynamics, in particular, is highly with GC content. We combine genome-wide time of replication (ToR) data, topological domains maps detailed functional annotations to study the correlations between timing content at find that decrease genomic large scale late replicating regions can be explained by mutation bias favoring A/T nucleotide, without selection or biased gene conversion. Quantification free dNTP pool during cell cycle consistent a mechanism involving replication-coupled spectrum favors AT nucleotides S-phase. suggest mammalian composition shaped independent forces, globally modulating locally selecting on element. Deconvoluting these forces analyzing them their native scales important for proper characterization complex correlations.

Language: Английский

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Novel ATP-cone-driven allosteric regulation of ribonucleotide reductase via the radical-generating subunit

eLife, Journal Year: 2018, Volume and Issue: 7

Published: Feb. 1, 2018

Ribonucleotide reductases (RNRs) are key enzymes in DNA metabolism, with allosteric mechanisms controlling substrate specificity and overall activity. In RNRs, the activity master-switch, ATP-cone, has been found exclusively catalytic subunit. two class I RNR subclasses whose subunit lacks we discovered ATP-cones radical-generating The ATP-cone Leeuwenhoekiella blandensis regulates via quaternary structure induced by binding of nucleotides. ATP induces enzymatically competent dimers, whereas dATP non-productive tetramers, resulting different holoenzymes. tetramer forms interactions between ATP-cones, shown a 2.45 Å crystal structure. We also present evidence for an MnIIIMnIV metal center. summary, lack domain was compensated transfer to To our knowledge, this represents first observation components same enzyme complex.

Language: Английский

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Role of exercise-induced hepatokines in metabolic disorders

AJP Endocrinology and Metabolism, Journal Year: 2019, Volume and Issue: 317(1), P. E11 - E24

Published: April 9, 2019

The health-promoting effects of physical activity to prevent and treat metabolic disorders are numerous. However, the underlying molecular mechanisms not yet completely deciphered. In recent years, studies have referred liver as an endocrine organ, since it releases specific proteins called hepatokines. Some these hepatokines involved in whole body homeostasis theorized participate development disease. this regard, present review describes role Fibroblast Growth Factor 21, Fetuin-A, Angiopoietin-like protein 4, Follistatin disease their production response acute exercise. Also, we discuss potential mediating beneficial regular exercise future challenges discovery new exercise-induced

Language: Английский

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Mutation, Randomness, and Evolution

Oxford University Press eBooks, Journal Year: 2021, Volume and Issue: unknown

Published: April 8, 2021

Abstract Mutation, Randomness, and Evolution presents a new understanding of how the course evolution may reflect biases in variation unites key concerns molecular microbial evolution, evo-devo, evolvability, self-organization by placing these on solid theoretical empirical foundation. It situates them within broader movement away from externalism towards focus internal details living systems, including their evolutionary causes predictable consequences. In neo-Darwinian theory, contrast, selection is potter clay: external does important work gets all credit, while merely supplies an abundance random raw materials. Indeed, one meanings randomness doctrine that any peculiarities or tendencies mutation are ultimately irrelevant. The theory determined externally, without dispositional role for factors, was particularly attractive before revolution, when biologists had little systematic knowledge factors. Today, scientists deeply immersed molecular, genetic, developmental life. potential factors rests recognition introduction process distinctive kind cause, not same thing (conceptually, historically, theoretically) as classical “force” mutation, but with different implications, ability to impose adaptive evolution. This predicted influence verified recent evidence episodes adaptation traced level.

Language: Английский

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