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Bioscience Reports Oct 2023DNA replication forks are subject to intricate surveillance and strict regulation by sophisticated cellular machinery. Such close regulation is necessary to ensure the... (Review)
Review
DNA replication forks are subject to intricate surveillance and strict regulation by sophisticated cellular machinery. Such close regulation is necessary to ensure the accurate duplication of genetic information and to tackle the diverse endogenous and exogenous stresses that impede this process. Stalled replication forks are vulnerable to collapse, which is a major cause of genomic instability and carcinogenesis. Replication stress responses, which are organized via a series of coordinated molecular events, stabilize stalled replication forks and carry out fork reversal and restoration. DNA damage tolerance and repair pathways such as homologous recombination and Fanconi anemia also contribute to replication fork stabilization. The signaling network that mediates the transduction and interplay of these pathways is regulated by a series of post-translational modifications, including ubiquitination, which affects the activity, stability, and interactome of substrates. In particular, the ubiquitination of replication protein A and proliferating cell nuclear antigen at stalled replication forks promotes the recruitment of downstream regulators. In this review, we describe the ubiquitination-mediated signaling cascades that regulate replication fork progression and stabilization. In addition, we discuss the targeting of replication fork stability and ubiquitination system components as a potential therapeutic approach for the treatment of cancer.
Topics: Humans; DNA Replication; Ubiquitination; DNA Damage; Genomic Instability; Homologous Recombination; Neoplasms
PubMed: 37728310
DOI: 10.1042/BSR20222591 -
Seminars in Cell & Developmental Biology May 2021DNA replication is laden with obstacles that slow, stall, collapse, and break DNA replication forks. At each obstacle, there is a decision to be made whether to bypass... (Review)
Review
DNA replication is laden with obstacles that slow, stall, collapse, and break DNA replication forks. At each obstacle, there is a decision to be made whether to bypass the lesion, repair or restart the damaged fork, or to protect stalled forks from further demise. Each "decision" draws upon multitude of proteins participating in various mechanisms that allow repair and restart of replication forks. Specific functions for many of these proteins have been described and an understanding of how they come together in supporting replication forks is starting to emerge. Many questions, however, remain regarding selection of the mechanisms that enable faithful genome duplication and how "normal" intermediates in these mechanisms are sometimes funneled into "rogue" processes that destabilize the genome and lead to cancer, cell death, and emergence of chemotherapeutic resistance. In this review we will discuss molecular mechanisms of DNA damage bypass and replication fork protection and repair. We will specifically focus on the key players that define which mechanism is employed including: PCNA and its control by posttranslational modifications, translesion synthesis DNA polymerases, molecular motors that catalyze reversal of stalled replication forks, proteins that antagonize fork reversal and protect reversed forks from nucleolytic degradation, and the machinery of homologous recombination that helps to reestablish broken forks. We will also discuss risks to genome integrity inherent in each of these mechanisms.
Topics: DNA Damage; DNA Replication; Humans
PubMed: 33967572
DOI: 10.1016/j.semcdb.2020.10.001 -
Genes To Cells : Devoted To Molecular &... Feb 2021Replication initiation, elongation and completion are tightly coordinated to ensure that all sequences replicate precisely once each generation. UV-induced DNA damage...
Replication initiation, elongation and completion are tightly coordinated to ensure that all sequences replicate precisely once each generation. UV-induced DNA damage disrupts replication and delays elongation, which may compromise this coordination leading to genome instability and cell death. Here, we profiled the Escherichia coli genome as it recovers from UV irradiation to determine how these replicational processes respond. We show that oriC initiations continue to occur, leading to copy number enrichments in this region. At late times, the combination of new oriC initiations and delayed elongating forks converging in the terminus appear to stress or impair the completion reaction, leading to a transient over-replication in this region of the chromosome. In mutants impaired for restoring elongation, including recA, recF and uvrA, the genome degrades or remains static, suggesting that cell death occurs early after replication is disrupted, leaving partially duplicated genomes. In mutants impaired for completing replication, including recBC, sbcCD xonA and recG, the recovery of elongation and initiation leads to a bottleneck, where the nonterminus region of the genome is amplified and accumulates, indicating that a delayed cell death occurs in these mutants, likely resulting from mis-segregation of unbalanced or unresolved chromosomes when cells divide.
Topics: Chromosomes, Bacterial; DNA Damage; DNA Repair; DNA Replication; Escherichia coli; Escherichia coli Proteins; Gene Dosage; Genome, Bacterial; Mutation; Ultraviolet Rays
PubMed: 33382157
DOI: 10.1111/gtc.12826 -
Current Opinion in Genetics &... Dec 2021Replication fork stalling occurs when the replisome encounters a barrier to normal fork progression. Replisome stalling events are common during scheduled DNA synthesis,... (Review)
Review
Replication fork stalling occurs when the replisome encounters a barrier to normal fork progression. Replisome stalling events are common during scheduled DNA synthesis, but vary in their severity. At one extreme, a lesion may induce only temporary pausing of a DNA polymerase; at the other, it may present a near-absolute barrier to the replicative helicase and effectively block fork progression. Many alternative pathways have evolved to respond to these different types of replication stress. Among these, the homologous recombination (HR) pathway plays an important role, protecting the stalled fork and processing it for repair. Here, we review recent advances in our understanding of how blocked replication forks in vertebrate cells can be processed for recombination and for replication restart.
Topics: Chromosomes; DNA Helicases; DNA Replication
PubMed: 34464818
DOI: 10.1016/j.gde.2021.08.003 -
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 -
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 -
Cold Spring Harbor Perspectives in... Apr 2010The discovery of the DNA double helix structure half a century ago immediately suggested a mechanism for its duplication by semi-conservative copying of the nucleotide... (Review)
Review
The discovery of the DNA double helix structure half a century ago immediately suggested a mechanism for its duplication by semi-conservative copying of the nucleotide sequence into two DNA daughter strands. Shortly after, a second fundamental step toward the elucidation of the mechanism of DNA replication was taken with the isolation of the first enzyme able to polymerize DNA from a template. In the subsequent years, the basic mechanism of DNA replication and its enzymatic machinery components were elucidated, mostly through genetic approaches and in vitro biochemistry. Most recently, the spatial and temporal organization of the DNA replication process in vivo within the context of chromatin and inside the intact cell are finally beginning to be elucidated. On the one hand, recent advances in genome-wide high throughput techniques are providing a new wave of information on the progression of genome replication at high spatial resolution. On the other hand, novel super-resolution microscopy techniques are just starting to give us the first glimpses of how DNA replication is organized within the context of single intact cells with high spatial resolution. The integration of these data with time lapse microscopy analysis will give us the ability to film and dissect the replication of the genome in situ and in real time.
Topics: Animals; Cell Cycle; DNA Replication; Epigenesis, Genetic; Genome; Humans; Microscopy, Confocal
PubMed: 20452942
DOI: 10.1101/cshperspect.a000737 -
Experimental Physiology Jan 2003Mitochondria are subcellular organelles, devoted mainly to energy production in the form of ATP, that contain their own genetic system. Mitochondrial DNA codifies a... (Review)
Review
Mitochondria are subcellular organelles, devoted mainly to energy production in the form of ATP, that contain their own genetic system. Mitochondrial DNA codifies a small, but essential number of polypeptides of the oxidative phosphorylation system. The mammalian mitochondrial genome is an example of extreme economy showing a compact gene organization. The coding sequences for two ribosomal RNAs (rRNAs), 22 transfer RNAs (tRNAs) and 13 polypeptides are contiguous and without introns. The tRNAs are regularly interspersed between the rRNA and protein-coding genes, playing a crucial role in RNA maturation from the polycistronic transcripts. A single major non-coding region, called the D-loop region, contains the main regulatory sequences for transcription and replication initiation. This genetic organization has its precise correspondence in the mode of expression and distinctive structural features of the RNAs. The basic mechanisms of mitochondrial DNA transcription and replication and the main cis-acting elements playing a role in both processes have been determined. Many trans-acting factors involved in mitochondrial gene expression, including the RNA and DNA polymerases, have been cloned or identified. However, the regulatory mechanisms participating in mitochondrial gene expression are still poorly understood. The interest to complete this knowledge is increased by the involvement of mitochondria in human diseases, in basic processes such as heat production, Ca(2+) homeostasis and apoptosis, and by their potential role in ageing and carcinogenesis.
Topics: Animals; DNA Replication; DNA, Mitochondrial; Gene Expression Regulation; Homeostasis; Humans; Mammals; Molecular Structure; RNA; RNA, Mitochondrial; Transcription, Genetic
PubMed: 12525854
DOI: 10.1113/eph8802514 -
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 -
Seminars in Cancer Biology Apr 2013Normal cellular division requires that the genome be faithfully replicated to ensure that unaltered genomic information is passed from one generation to the next. DNA... (Review)
Review
Normal cellular division requires that the genome be faithfully replicated to ensure that unaltered genomic information is passed from one generation to the next. DNA replication initiates from thousands of origins scattered throughout the genome every cell cycle; however, not all origins initiate replication at the same time. A vast amount of work over the years indicates that different origins along each eukaryotic chromosome are activated in early, middle or late S phase. This temporal control of DNA replication is referred to as the replication-timing program. The replication-timing program represents a very stable epigenetic feature of chromosomes. Recent evidence has indicated that the replication-timing program can influence the spatial distribution of mutagenic events such that certain regions of the genome experience increased spontaneous mutagenesis compared to surrounding regions. This influence has helped shape the genomes of humans and other multicellular organisms and can affect the distribution of mutations in somatic cells. It is also becoming clear that the replication-timing program is deregulated in many disease states, including cancer. Aberrant DNA replication timing is associated with changes in gene expression, changes in epigenetic modifications and an increased frequency of structural rearrangements. Furthermore, certain replication timing changes can directly lead to overt genomic instability and may explain unique mutational signatures that are present in cells that have undergone the recently described processes of "chromothripsis" and "kataegis". In this review, we will discuss how the normal replication timing program, as well as how alterations to this program, can contribute to the evolution of the genomic landscape in normal and cancerous cells.
Topics: Animals; DNA Replication; DNA Replication Timing; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Genomic Instability; Humans; Models, Biological; Neoplasms; Time Factors
PubMed: 23327985
DOI: 10.1016/j.semcancer.2013.01.001