Regulation of the Initiation of DNA Replication upon DNA Damage in Eukaryotes

Köhler, Kerstin; Ferreira, Pedro; Pfander, Boris; Boos, Dominik

doi:10.1007/978-3-319-24696-3_22

Cited by 6 publications

(4 citation statements)

References 80 publications

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“…DSB's as well as base modifications, single-strand breaks (SSBs), double strand breaks (DSBs), and interstrand cross-links (ICLs) result from DNA damages that abnormally alter genetic structure and prevent the proper functioning of replication [103,104].…”

Section: Effect Of Redundancy Loss On Differential Programmatic Chara...mentioning

confidence: 99%

On the Origin of Aging by Means of Natural Selection

Walker

2023

Preprint

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Formulating a novel concept about the origin of human aging has been constrained by the dominance of a “classic theory” that was proposed nearly 70 years ago. Despite concern over the validity of some of its assumptions, the theory remained basic to our understanding of aging’s relationship with natural selection (NS). However, the logic upon which it rests was tested and subsequently challenged. The present theory describes the single cause of human aging consistent with Darwin’s evolutionary requirement for selection of adaptive traits. It describes an emergent property of the developmental program (DP), that is expressed upon completion of ontogenesis. It involves redundant expression of regulatory processes from the last stage of the DP. That mechanism subsequently preserves a non-aging, stable interval of unchanging NS during which reproductive fitness is achieved. Thereafter, loss of DP regulatory redundancy due to reliability limits, stochastic mutation accumulation, reproductive and a specific type of DNA damage, initiates aging which causes an inexorable decline in strength of NS to begin. It starts approximately a decade later than proposed in the classic theory. Since reproduction and aging are inextricably linked by the same emergent property, selection of that regulatory mechanism makes both traits products of NS.

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Section: Effect Of Redundancy Loss On Differential Programmatic Chara...mentioning

confidence: 99%

On the Origin of Aging by Means of Natural Selection

Walker

2023

Preprint

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“…DNA damage is a constant threat arising from both internal and external agents. DNA adducts, when formed, have the potential to cause mutations that can subsequently lead to diseases and the death of cells . DNA undergoes spontaneous hydrolysis inside the cell, affecting its phosphodiester, N -glycosylic, and amino bonds.…”

Section: Introductionmentioning

confidence: 99%

Effects of the Y432S Cancer-Associated Variant on the Reaction Mechanism of Human DNA Polymerase κ

Maghsoud,

Roy,

Leddin

et al. 2024

J. Chem. Inf. Model.

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Human DNA polymerases are vital for genetic information management. Their function involves catalyzing the synthesis of DNA strands with unparalleled accuracy, which ensures the fidelity and stability of the human genomic blueprint. Several disease-associated mutations and their functional impact on DNA polymerases have been reported. One particular polymerase, human DNA polymerase kappa (Pol κ), has been reported to be susceptible to several cancer-associated mutations. The Y432S mutation in Pol κ, associated with various cancers, is of interest due to its impact on polymerization activity and markedly reduced thermal stability. Here, we have used computational simulations to investigate the functional consequences of the Y432S using classical molecular dynamics (MD) and coupled quantum mechanics/molecular mechanics (QM/MM) methods. Our findings suggest that Y432S induces structural alterations in domains responsible for nucleotide addition and ternary complex stabilization while retaining structural features consistent with possible catalysis in the active site. Calculations of the minimum energy path associated with the reaction mechanism of the wild type (WT) and Y432S Pol κ indicate that, while both enzymes are catalytically competent (in terms of energetics and the active site's geometries), the cancer mutation results in an endoergic reaction and an increase in the catalytic barrier. Interactions with a third magnesium ion and environmental effects on nonbonded interactions, particularly involving key residues, contribute to the kinetic and thermodynamic distinctions between the WT and mutant during the catalytic reaction. The energetics and electronic findings suggest that active site residues favor the catalytic reaction with dCTP 3− over dCTP 4− .

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“…DNA adducts, when formed, have the potential to cause mutations that can subsequently lead to diseases and the death of cells. 1 DNA undergoes spontaneous hydrolysis inside the cell, affecting its phosphodiester, N-glycosylic, and amino bonds. Additionally, DNA is under constant attack by oxygen free radicals, which harm the sugar and bases.…”

Section: Introductionmentioning

confidence: 99%

Effects of the Y432S Cancer-Associated Variant on the Reaction Mechanism of Human DNA Polymerase κ

Maghsoud,

Roy,

Leddin

et al. 2024

Preprint

View full text Add to dashboard Cite

Human polymerases are vital for genetic information management. Their function involves catalyzing the synthesis of DNA strands with unparalleled accuracy, which ensures the fidelity and stability of the human genomic blueprint. Several disease-associated mutations and their functional impact on DNA polymerases have been reported. One particular polymerase, human DNA polymerase kappa (Pol κ), has been reported to be susceptible to several cancer-associated mutations. The Y432S mutation in Pol κ, which is associated with various cancers, is of interest due to its impact on polymerization activity and markedly reduced thermal stability. Here, we have used computational simulations to investigate the functional consequences of the Y432S by means of classical molecular dynamics (MD) and coupled quantum mechanics/molecular mechanics (QM/MM) methods. Our results suggest that Y432S results in structural effects on domains involved in nucleotide addition and ternary complex stabilization while maintaining catalytic competence. Calculation of the minimum energy path associated with the reaction mechanism of wild type (WT) and Y432S Pol κ indicate that while both enzymes are catalytically competent, the cancer mutation results in a slightly endoergic reaction and an increase in the catalytic barrier. Interactions with a third magnesium ion and environmental effects on non-bonded interactions, particularly involving key residues, contribute to the kinetic and thermodynamic distinctions between the WT and mutant during the catalytic reaction. The energetics and electronic findings suggest that active site residues favor the catalytic reaction with dCTP3– over dCTP4–.

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Regulation of the Initiation of DNA Replication upon DNA Damage in Eukaryotes

Cited by 6 publications

References 80 publications

On the Origin of Aging by Means of Natural Selection

On the Origin of Aging by Means of Natural Selection

Effects of the Y432S Cancer-Associated Variant on the Reaction Mechanism of Human DNA Polymerase κ

Effects of the Y432S Cancer-Associated Variant on the Reaction Mechanism of Human DNA Polymerase κ

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