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Cancer Science Feb 2018DNA replication is one of the fundamental biological processes in which dysregulation can cause genome instability. This instability is one of the hallmarks of cancer... (Review)
Review
DNA replication is one of the fundamental biological processes in which dysregulation can cause genome instability. This instability is one of the hallmarks of cancer and confers genetic diversity during tumorigenesis. Numerous experimental and clinical studies have indicated that most tumors have experienced and overcome the stresses caused by the perturbation of DNA replication, which is also referred to as DNA replication stress (DRS). When we consider therapeutic approaches for tumors, it is important to exploit the differences in DRS between tumor and normal cells. In this review, we introduce the current understanding of DRS in tumors and discuss the underlying mechanism of cancer therapy from the aspect of DRS.
Topics: DNA Damage; DNA Replication; Gene Regulatory Networks; Genomic Instability; Humans; Neoplasms
PubMed: 29168596
DOI: 10.1111/cas.13455 -
Nucleus (Austin, Tex.) Dec 2023In eukaryotic genomes, hundreds to thousands of potential start sites of DNA replication named origins are dispersed across each of the linear chromosomes. During... (Review)
Review
In eukaryotic genomes, hundreds to thousands of potential start sites of DNA replication named origins are dispersed across each of the linear chromosomes. During S-phase, only a subset of origins is selected in a stochastic manner to assemble bidirectional replication forks and initiate DNA synthesis. Despite substantial progress in our understanding of this complex process, a comprehensive 'identity code' that defines origins based on specific nucleotide sequences, DNA structural features, the local chromatin environment, or 3D genome architecture is still missing. In this article, we review the genetic and epigenetic features of replication origins in yeast and metazoan chromosomes and highlight recent insights into how this flexibility in origin usage contributes to nuclear organization, cell growth, differentiation, and genome stability.
Topics: Animals; Replication Origin; DNA Replication; Chromatin; DNA; Saccharomyces cerevisiae
PubMed: 37469113
DOI: 10.1080/19491034.2023.2229642 -
Cold Spring Harbor Perspectives in... May 2016The genome is subject to a diverse array of epigenetic modifications from DNA methylation to histone posttranslational changes. Many of these marks are somatically... (Review)
Review
The genome is subject to a diverse array of epigenetic modifications from DNA methylation to histone posttranslational changes. Many of these marks are somatically stable through cell division. This article focuses on our knowledge of the mechanisms governing the inheritance of epigenetic marks, particularly, repressive ones, when the DNA and chromatin template are duplicated in S phase. This involves the action of histone chaperones, nucleosome-remodeling enzymes, histone and DNA methylation binding proteins, and chromatin-modifying enzymes. Last, the timing of DNA replication is discussed, including the question of whether this constitutes an epigenetic mark that facilitates the propagation of epigenetic marks.
Topics: DNA Methylation; DNA Replication; Epigenesis, Genetic; Gene Expression Regulation; Histone Chaperones; Histone Code; Models, Genetic; Protein Processing, Post-Translational
PubMed: 27141050
DOI: 10.1101/cshperspect.a019372 -
Genes Jun 2023This article reviews the currently used therapeutic strategies to target DNA replication stress for cancer treatment in the clinic, highlighting their effectiveness and... (Review)
Review
This article reviews the currently used therapeutic strategies to target DNA replication stress for cancer treatment in the clinic, highlighting their effectiveness and limitations due to toxicity and drug resistance. Cancer cells experience enhanced spontaneous DNA damage due to compromised DNA replication machinery, elevated levels of reactive oxygen species, loss of tumor suppressor genes, and/or constitutive activation of oncogenes. Consequently, these cells are addicted to DNA damage response signaling pathways and repair machinery to maintain genome stability and support survival and proliferation. Chemotherapeutic drugs exploit this genetic instability by inducing additional DNA damage to overwhelm the repair system in cancer cells. However, the clinical use of DNA-damaging agents is limited by their toxicity and drug resistance often arises. To address these issues, the article discusses a potential strategy to target the cancer-associated isoform of proliferating cell nuclear antigen (caPCNA), which plays a central role in the DNA replication and damage response network. Small molecule and peptide agents that specifically target caPCNA can selectively target cancer cells without significant toxicity to normal cells or experimental animals.
Topics: Animals; Neoplasms; DNA Replication; DNA Damage; Oncogenes
PubMed: 37510250
DOI: 10.3390/genes14071346 -
Nature Genetics Mar 2022Totipotency emerges in early embryogenesis, but its molecular underpinnings remain poorly characterized. In the present study, we employed DNA fiber analysis to...
Totipotency emerges in early embryogenesis, but its molecular underpinnings remain poorly characterized. In the present study, we employed DNA fiber analysis to investigate how pluripotent stem cells are reprogrammed into totipotent-like 2-cell-like cells (2CLCs). We show that totipotent cells of the early mouse embryo have slow DNA replication fork speed and that 2CLCs recapitulate this feature, suggesting that fork speed underlies the transition to a totipotent-like state. 2CLCs emerge concomitant with DNA replication and display changes in replication timing (RT), particularly during the early S-phase. RT changes occur prior to 2CLC emergence, suggesting that RT may predispose to gene expression changes and consequent reprogramming of cell fate. Slowing down replication fork speed experimentally induces 2CLCs. In vivo, slowing fork speed improves the reprogramming efficiency of somatic cell nuclear transfer. Our data suggest that fork speed regulates cellular plasticity and that remodeling of replication features leads to changes in cell fate and reprogramming.
Topics: Animals; Cell Differentiation; Cellular Reprogramming; DNA Replication; Embryo, Mammalian; Embryonic Development; Mice; Pluripotent Stem Cells
PubMed: 35256805
DOI: 10.1038/s41588-022-01023-0 -
Genes Apr 2023Mutations of numerous genes involved in DNA replication, DNA repair, and DNA damage response (DDR) pathways lead to a variety of human diseases, including aging and...
Mutations of numerous genes involved in DNA replication, DNA repair, and DNA damage response (DDR) pathways lead to a variety of human diseases, including aging and cancer [...].
Topics: Humans; DNA Damage; DNA Repair; Mutation; Neoplasms; DNA Replication
PubMed: 37107651
DOI: 10.3390/genes14040893 -
Annual Review of Genetics Nov 2023Transcription and replication both require large macromolecular complexes to act on a DNA template, yet these machineries cannot simultaneously act on the same DNA... (Review)
Review
Transcription and replication both require large macromolecular complexes to act on a DNA template, yet these machineries cannot simultaneously act on the same DNA sequence. Conflicts between the replication and transcription machineries (transcription-replication conflicts, or TRCs) are widespread in both prokaryotes and eukaryotes and have the capacity to both cause DNA damage and compromise complete, faithful replication of the genome. This review will highlight recent studies investigating the genomic locations of TRCs and the mechanisms by which they may be prevented, mitigated, or resolved. We address work from both model organisms and mammalian systems but predominantly focus on multicellular eukaryotes owing to the additional complexities inherent in the coordination of replication and transcription in the context of cell type-specific gene expression and higher-order chromatin organization.
Topics: Animals; Transcription, Genetic; DNA Replication; Genomic Instability; Eukaryota; DNA Damage; Mammals
PubMed: 37552891
DOI: 10.1146/annurev-genet-080320-031523 -
Seminars in Cell & Developmental Biology Dec 2022Every time a cell copies its DNA the genetic material is exposed to the acquisition of mutations and genomic alterations that corrupt the information passed on to... (Review)
Review
Every time a cell copies its DNA the genetic material is exposed to the acquisition of mutations and genomic alterations that corrupt the information passed on to daughter cells. A tight temporal regulation of DNA replication is necessary to ensure the full copy of the DNA while preventing the appearance of genomic instability. Protein modification by ubiquitin and SUMO constitutes a very complex and versatile system that allows the coordinated control of protein stability, activity and interactome. In chromatin, their action is complemented by the AAA+ ATPase VCP/p97 that recognizes and removes ubiquitylated and SUMOylated factors from specific cellular compartments. The concerted action of the ubiquitin/SUMO system and VCP/p97 determines every step of DNA replication enforcing the ordered activation/inactivation, loading/unloading and stabilization/destabilization of replication factors. Here we analyze the mechanisms used by ubiquitin/SUMO and VCP/p97 to establish molecular timers throughout DNA replication and their relevance in maintaining genome stability. We propose that these PTMs are the main molecular watch of DNA replication from origin recognition to replisome disassembly.
Topics: Humans; Cell Cycle Proteins; DNA; DNA Repair; DNA Replication; Genomic Instability; Ubiquitin; Sumoylation; Ubiquitination; Small Ubiquitin-Related Modifier Proteins
PubMed: 35210137
DOI: 10.1016/j.semcdb.2022.02.013 -
Cell Oct 2019DNA-replication machinery introduces intertwining and supercoiling of DNA strands as it traverses the double helix, which could impede replication and compromise genome...
DNA-replication machinery introduces intertwining and supercoiling of DNA strands as it traverses the double helix, which could impede replication and compromise genome stability. A new study in Cell shows that the intrinsic physical properties of chromatin fibers dictate how torsional stress is partitioned to minimize these risks and facilitate DNA replication.
Topics: Chromatin; DNA; DNA Replication; Genomic Instability; Humans
PubMed: 31626764
DOI: 10.1016/j.cell.2019.09.026 -
Aging Dec 2017
Topics: Animals; CDC2 Protein Kinase; Cell Cycle; Cell Cycle Proteins; DNA Replication; Humans
PubMed: 29242409
DOI: 10.18632/aging.101348