DNA Replication Stress Tolerance Mechanisms: From Nucleoside Analog Repair to Therapeutic Strategies

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Genetics".

Deadline for manuscript submissions: 31 July 2026 | Viewed by 91

Special Issue Editors


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Guest Editor
Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Hachioji-shi, Japan
Interests: nucleoside analog; DNA repair; replication; recombination; gene expression; epigenetics; gene expression and chromatin biology; gene regulation; DNA damage
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E-Mail Website
Guest Editor
Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Hachioji-shi, Japan
Interests: nucleoside analog; DNA repair; replication; recombination; DNA damage; sister chromatid cohesion; chromosome segregation

Special Issue Information

Dear Colleagues,

We are pleased to invite you to publish your work in the Special Issue entitled “DNA Replication Stress Tolerance Mechanisms: From Nucleoside Analog Repair to Therapeutic Strategies”.

Genomic DNA is continuously challenged by endogenous and exogenous sources of damage, and replication reactions are halted at damaged templates. Prolonged replication arrest results in replication fork collapse and ultimately leads to cell death. To avoid replication arrest upon damaged template, cells evolved several mechanisms named DNA damage tolerance (DDT) mechanisms, such as translesion DNA synthesis (TLS), homologous recombination (HR) mediated template switch, repriming of replication, and fork regression via fork reversal. Nucleoside analogs are chemical compounds structurally similar to the nucleosides (dA, dC, dG, and dT) that constitute DNA molecules. These compounds have been widely used in the treatment of cancer and viral infections due to their inhibitory effect on replication. However, the precise effects of each nucleoside on replication and DDT mechanisms involved in the individual nucleoside analog have not been well elucidated. Moreover, the cellular effects of individual nucleoside analogs on cancer cells, which possess genome instability with compromised DNA damage response systems, including DDT, DNA repair, and DNA damage checkpoint, have remained elusive.

This Special Issue aims to introduce to the scientific community the role of DNA damage response systems, including DDT, DNA repair, and DNA damage checkpoint in cellular tolerance to nucleoside analogs and to address possible directions for developing new therapeutic strategies using nucleoside analogs by targeting weakened DNA damage response systems in cancers.

We are seeking original articles as well as reviews on the cellular effects of nucleoside analogs and therapeutic strategies targeting the DNA damage response systems. Articles reporting research on the general mechanisms responsible for replication stress tolerance and phenotypic analyses of mutant cell lines associated with DNA replication modulation are also welcome.

I am looking forward to receiving your contributions

Prof. Dr. Kouji Hirota
Dr. Ryotaro Kawasumi
Guest Editors

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Keywords

  • nucleoside analogs
  • DNA replication
  • DNA damage tolerance
  • DNA repair
  • DNA damage checkpoint
  • targeted cancer therapy

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Published Papers (1 paper)

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Research

18 pages, 5031 KB  
Article
Generation of Human Haematopoietic Model Cell Lines Revealed Distinct Replication Stress Tolerance Between Two Oncogenic KRAS Mutations, G12V and A146T
by Mone Okuda, Ryotaro Kawasumi, Kayoko Tanaka and Kouji Hirota
Biomolecules 2026, 16(2), 204; https://doi.org/10.3390/biom16020204 (registering DOI) - 28 Jan 2026
Abstract
KRAS is one of the most frequently mutated genes in all human cancers, and its oncogenic mutation hotspots are glycine 12 (G12), glycine 13 (G13), glutamine 61 (Q61) and alanine 146 (A146). Among these hotspot mutations, A146 substitution mutations (A146X) occur relatively infrequently, [...] Read more.
KRAS is one of the most frequently mutated genes in all human cancers, and its oncogenic mutation hotspots are glycine 12 (G12), glycine 13 (G13), glutamine 61 (Q61) and alanine 146 (A146). Among these hotspot mutations, A146 substitution mutations (A146X) occur relatively infrequently, except for haematopoietic and lymphoid cancers, suggesting that A146X causes intrinsically distinct KRAS signalling compared to other KRAS oncogenic alleles. However, due to the absence of model A146X cell lines derived from haematopoietic sources, the cellular mechanisms that cause the differences between KRAS.A146X and other common KRAS mutants, such as KRAS.G12X, remain largely unexplored. In this study, we developed a set of isogenic model haematopoietic cell lines expressing KRAS.A146T, KRAS.G12V and KRAS.G12G (non-mutated) from the endogenous locus by genetically modifying the human lymphoblastoid TK6 cell line. We found that TK6 cells carrying KRASA146T/+ or KRASG12V/+ exhibited increased replication stress compared to KRAS wild-type cells. Strikingly, KRASA146T/+ cells strongly rely on PrimPol for maintaining cellular survival upon replication stress. In contrast, KRASG12V/+ cells exhibited hypersensitivity to inhibitors for the ATR-Chk1 checkpoint signalling axis and to nucleoside analogues commonly used to treat cancers and viral infections. Our findings demonstrate that the endogenously expressed oncogenic KRAS mutations exacerbate the replication stress and reveal KRAS allele-specific replication phenotypes, facilitating the development of effective chemotherapies tailored to specific oncogenic KRAS mutation alleles and types of cancer. Moreover, our study offers valuable model cell lines for investigating mechanisms underlying replication vulnerability in cancers harbouring oncogenic KRAS mutations. Full article
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