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Bioscience Reports Aug 2017In this summary, we focus on fundamental biology of Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR)-Cas (CRISPR-associated proteins) adaptive...
In this summary, we focus on fundamental biology of Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR)-Cas (CRISPR-associated proteins) adaptive immunity in bacteria. Emphasis is placed on emerging information about functional interplay between Cas proteins and proteins that remodel DNA during homologous recombination (HR), DNA replication or DNA repair. We highlight how replication forks may act as 'trigger points' for CRISPR adaptation events, and the potential for cascade-interference complexes to act as precise roadblocks in DNA replication by an invader MGE (mobile genetic element), without the need for DNA double-strand breaks.
Topics: Bacteria; CRISPR-Cas Systems; DNA Repair; DNA Replication; DNA, Bacterial; Homologous Recombination
PubMed: 28674106
DOI: 10.1042/BSR20160297 -
International Journal of Molecular... Mar 2021Several lines of evidence suggest the existence in the eukaryotic cells of a tight, yet largely unexplored, connection between DNA replication and sister chromatid... (Review)
Review
Several lines of evidence suggest the existence in the eukaryotic cells of a tight, yet largely unexplored, connection between DNA replication and sister chromatid cohesion. Tethering of newly duplicated chromatids is mediated by cohesin, an evolutionarily conserved hetero-tetrameric protein complex that has a ring-like structure and is believed to encircle DNA. Cohesin is loaded onto chromatin in telophase/G1 and converted into a cohesive state during the subsequent S phase, a process known as cohesion establishment. Many studies have revealed that down-regulation of a number of DNA replication factors gives rise to chromosomal cohesion defects, suggesting that they play critical roles in cohesion establishment. Conversely, loss of cohesin subunits (and/or regulators) has been found to alter DNA replication fork dynamics. A critical step of the cohesion establishment process consists in cohesin acetylation, a modification accomplished by dedicated acetyltransferases that operate at the replication forks. Defects in cohesion establishment give rise to chromosome mis-segregation and aneuploidy, phenotypes frequently observed in pre-cancerous and cancerous cells. Herein, we will review our present knowledge of the molecular mechanisms underlying the functional link between DNA replication and cohesion establishment, a phenomenon that is unique to the eukaryotic organisms.
Topics: Animals; Cell Cycle Proteins; Chromatids; Chromosomal Proteins, Non-Histone; Chromosome Segregation; DNA Replication; G1 Phase; Humans; Telophase; Cohesins
PubMed: 33802105
DOI: 10.3390/ijms22062810 -
The FEBS Journal May 2018The term hypoxia refers to any condition where insufficient oxygen is available and therefore encompasses a range of actual oxygen concentrations. The regions of tumours... (Review)
Review
The term hypoxia refers to any condition where insufficient oxygen is available and therefore encompasses a range of actual oxygen concentrations. The regions of tumours adjacent to necrotic areas are at almost anoxic levels and are known to be extremely therapy resistant (radiobiological hypoxia). The biological response to radiobiological hypoxia includes the rapid accumulation of replication stress and subsequent DNA damage response, including both ATR- and ATM-mediated signalling, despite the absence of detectable DNA damage. The causes and consequences of hypoxia-induced replication stress will be discussed.
Topics: Animals; Cell Cycle Proteins; Cell Hypoxia; DNA Damage; DNA Repair; DNA Replication; DNA-Binding Proteins; Deoxyribonucleotides; Humans; Neoplasms; Oxygen; Ribonucleotide Reductases; Stress, Physiological; Tumor Microenvironment
PubMed: 29288533
DOI: 10.1111/febs.14377 -
Trends in Microbiology Mar 2018Chromosomal DNA replication starts at a specific region called an origin of replication. Until recently, all organisms were thought to require origins to replicate their... (Review)
Review
Chromosomal DNA replication starts at a specific region called an origin of replication. Until recently, all organisms were thought to require origins to replicate their chromosomes. It was recently discovered that some archaeal species do not utilize origins of replication under laboratory growth conditions.
Topics: Archaea; Archaeal Proteins; Chromosomes, Archaeal; DNA Replication; DNA, Archaeal; Genes, Archaeal; Microbial Viability; Replication Origin
PubMed: 29268981
DOI: 10.1016/j.tim.2017.12.001 -
DNA Repair Sep 2023The perturbation of DNA replication, a phenomena termed "replication stress", is a driving force of genome instability and a hallmark of cancer cells. Among the DNA... (Review)
Review
The perturbation of DNA replication, a phenomena termed "replication stress", is a driving force of genome instability and a hallmark of cancer cells. Among the DNA repair mechanisms that contribute to tolerating replication stress, the homologous recombination pathway is central to the alteration of replication fork progression. In many organisms, defects in the homologous recombination machinery result in increased cell sensitivity to replication-blocking agents and a higher risk of cancer in humans. Moreover, the status of homologous recombination in cancer cells often correlates with the efficacy of anti-cancer treatment. In this review, we discuss our current understanding of the different functions of homologous recombination in fixing replication-associated DNA damage and contributing to complete genome duplication. We also examine which functions are pivotal in preventing cancer and genome instability.
Topics: Humans; DNA Replication; DNA Damage; Homologous Recombination; DNA Repair; Genomic Instability
PubMed: 37541027
DOI: 10.1016/j.dnarep.2023.103548 -
Nature Communications Mar 2023Elevated levels of reactive oxygen species (ROS) reduce replication fork velocity by causing dissociation of the TIMELESS-TIPIN complex from the replisome. Here, we show...
Elevated levels of reactive oxygen species (ROS) reduce replication fork velocity by causing dissociation of the TIMELESS-TIPIN complex from the replisome. Here, we show that ROS generated by exposure of human cells to the ribonucleotide reductase inhibitor hydroxyurea (HU) promote replication fork reversal in a manner dependent on active transcription and formation of co-transcriptional RNA:DNA hybrids (R-loops). The frequency of R-loop-dependent fork stalling events is also increased after TIMELESS depletion or a partial inhibition of replicative DNA polymerases by aphidicolin, suggesting that this phenomenon is due to a global replication slowdown. In contrast, replication arrest caused by HU-induced depletion of deoxynucleotides does not induce fork reversal but, if allowed to persist, leads to extensive R-loop-independent DNA breakage during S-phase. Our work reveals a link between oxidative stress and transcription-replication interference that causes genomic alterations recurrently found in human cancer.
Topics: Humans; Reactive Oxygen Species; DNA Replication; S Phase; DNA-Binding Proteins; Hydroxyurea; DNA
PubMed: 36997515
DOI: 10.1038/s41467-023-37341-y -
International Journal of Molecular... Jan 2021Deoxyribonucleic acid (DNA) replication can be divided into three major steps: initiation, elongation and termination. Each time a human cell divides, these steps must... (Review)
Review
Deoxyribonucleic acid (DNA) replication can be divided into three major steps: initiation, elongation and termination. Each time a human cell divides, these steps must be reiteratively carried out. Disruption of DNA replication can lead to genomic instability, with the accumulation of point mutations or larger chromosomal anomalies such as rearrangements. While cancer is the most common class of disease associated with genomic instability, several congenital diseases with dysfunctional DNA replication give rise to similar DNA alterations. In this review, we discuss all congenital diseases that arise from pathogenic variants in essential replication genes across the spectrum of aberrant replisome assembly, origin activation and DNA synthesis. For each of these conditions, we describe their clinical phenotypes as well as molecular studies aimed at determining the functional mechanisms of disease, including the assessment of genomic stability. By comparing and contrasting these diseases, we hope to illuminate how the disruption of DNA replication at distinct steps affects human health in a surprisingly cell-type-specific manner.
Topics: Craniosynostoses; DNA Replication; Genomic Instability; Humans; Mutation; Neoplasms; Phenotype; RecQ Helicases
PubMed: 33477564
DOI: 10.3390/ijms22020911 -
Comptes Rendus Biologies Sep 2023Replication stress is an alteration in the progression of replication forks caused by a variety of events of endogenous or exogenous origin. In precancerous lesions,... (Review)
Review
Replication stress is an alteration in the progression of replication forks caused by a variety of events of endogenous or exogenous origin. In precancerous lesions, this stress is exacerbated by the deregulation of oncogenic pathways, which notably disrupts the coordination between replication and transcription, and leads to genetic instability and cancer development. It is now well established that transcription can interfere with genome replication in different ways, such as head-on collisions between polymerases, accumulation of positive DNA supercoils or formation of R-loops. These structures form during transcription when nascent RNA reanneals with DNA behind the RNA polymerase, forming a stable DNA:RNA hybrid. In this review, we discuss how these different cotranscriptional processes disrupt the progression of replication forks and how they contribute to genetic instability in cancer cells.
Topics: Transcription, Genetic; R-Loop Structures; DNA Replication; DNA; Oncogenes; RNA; Neoplasms
PubMed: 37779381
DOI: 10.5802/crbiol.123 -
PLoS Biology Mar 2021Faithful replication of the entire genome requires replication forks to copy large contiguous tracts of DNA, and sites of persistent replication fork stalling present a...
Faithful replication of the entire genome requires replication forks to copy large contiguous tracts of DNA, and sites of persistent replication fork stalling present a major threat to genome stability. Understanding the distribution of sites at which replication forks stall, and the ensuing fork processing events, requires genome-wide methods that profile replication fork position and the formation of recombinogenic DNA ends. Here, we describe Transferase-Activated End Ligation sequencing (TrAEL-seq), a method that captures single-stranded DNA 3' ends genome-wide and with base pair resolution. TrAEL-seq labels both DNA breaks and replication forks, providing genome-wide maps of replication fork progression and fork stalling sites in yeast and mammalian cells. Replication maps are similar to those obtained by Okazaki fragment sequencing; however, TrAEL-seq is performed on asynchronous populations of wild-type cells without incorporation of labels, cell sorting, or biochemical purification of replication intermediates, rendering TrAEL-seq far simpler and more widely applicable than existing replication fork direction profiling methods. The specificity of TrAEL-seq for DNA 3' ends also allows accurate detection of double-strand break sites after the initiation of DNA end resection, which we demonstrate by genome-wide mapping of meiotic double-strand break hotspots in a dmc1Δ mutant that is competent for end resection but not strand invasion. Overall, TrAEL-seq provides a flexible and robust methodology with high sensitivity and resolution for studying DNA replication and repair, which will be of significant use in determining mechanisms of genome instability.
Topics: 3' Untranslated Regions; Animals; DNA; DNA Breaks, Double-Stranded; DNA Repair; DNA Replication; DNA-Binding Proteins; Genome; Humans; Sequence Analysis, DNA
PubMed: 33760805
DOI: 10.1371/journal.pbio.3000886 -
Cell Cycle (Georgetown, Tex.) Apr 2021Accurate and complete DNA replication and separation are essential for genetic information inheritance and organism maintenance. Errors in DNA duplication are the main... (Review)
Review
Accurate and complete DNA replication and separation are essential for genetic information inheritance and organism maintenance. Errors in DNA duplication are the main source of genetic instability. Understanding DNA duplication regulation is the key to elucidate the mechanisms and find treatment strategies for human genetic disorders, especially cancer. The mechanistic target of rapamycin (mTOR) is a central regulator of cell growth and proliferation by integrating and processing extracellular and intracellular signals to monitor the well-being of cell physiology. mTOR signaling dysregulation is associated with many human diseases including cancer and diabetes. Emerging evidence has demonstrated that mTOR signaling plays a key role in DNA duplication. We herein review the current knowledge of mTOR signaling in the regulation of DNA replication origin licensing, replication fork progression, and stabilization.
Topics: Animals; Cell Proliferation; DNA Replication; Humans; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 33691584
DOI: 10.1080/15384101.2021.1897271