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Cold Spring Harbor Perspectives in... Jul 2013The accurate copying of genetic information in the double helix of DNA is essential for inheritance of traits that define the phenotype of cells and the organism. The... (Review)
Review
The accurate copying of genetic information in the double helix of DNA is essential for inheritance of traits that define the phenotype of cells and the organism. The core machineries that copy DNA are conserved in all three domains of life: bacteria, archaea, and eukaryotes. This article outlines the general nature of the DNA replication machinery, but also points out important and key differences. The most complex organisms, eukaryotes, have to coordinate the initiation of DNA replication from many origins in each genome and impose regulation that maintains genomic integrity, not only for the sake of each cell, but for the organism as a whole. In addition, DNA replication in eukaryotes needs to be coordinated with inheritance of chromatin, developmental patterning of tissues, and cell division to ensure that the genome replicates once per cell division cycle.
Topics: Archaea; Bacteria; DNA Damage; DNA Replication; Eukaryota; Models, Genetic
PubMed: 23818497
DOI: 10.1101/cshperspect.a010108 -
Biochemical and Biophysical Research... Dec 2022Nearly 70 years after the proposal of semiconservative replication of generic material by Watson and Crick, we now understand many of the proteins involved in the... (Review)
Review
Nearly 70 years after the proposal of semiconservative replication of generic material by Watson and Crick, we now understand many of the proteins involved in the replication of host chromosomes and how they operate. The initiator and replicator, proposed in the replicon hypothesis, are now well defined in both prokaryotes and eukaryotes. On the other hand, studies in prokaryotes and Archaea indicate alternative modes of initiation, which may not depend on an initiator. Here I summarize recent progress in the field of DNA replication and discuss the evolution of replication systems.
Topics: Replication Origin; DNA Replication; Escherichia coli; DNA-Binding Proteins; Replicon; Bacterial Proteins; Chromosomes, Bacterial; DNA, Bacterial
PubMed: 36344169
DOI: 10.1016/j.bbrc.2022.09.060 -
DNA Repair Jul 2021In every cell cycle, billions of nucleotides need to be duplicated within hours, with extraordinary precision and accuracy. The molecular mechanism by which cells... (Review)
Review
In every cell cycle, billions of nucleotides need to be duplicated within hours, with extraordinary precision and accuracy. The molecular mechanism by which cells regulate the replication event is very complicated, and the entire process begins way before the onset of S phase. During the G1 phase of the cell cycle, cells prepare by assembling essential replication factors to establish the pre-replicative complex at origins, sites that dictate where replication would initiate during S phase. During S phase, the replication process is tightly coupled with the DNA repair system to ensure the fidelity of replication. Defects in replication and any error must be recognized by DNA damage response and checkpoint signaling pathways in order to halt the cell cycle before cells are allowed to divide. The coordination of these processes throughout the cell cycle is therefore critical to achieve genomic integrity and prevent diseases. In this review, we focus on the current understanding of how the replication initiation events are regulated to achieve genome stability.
Topics: Animals; Cell Cycle; DNA Replication; Eukaryota; Genomic Instability; Humans; Replication Origin
PubMed: 33992866
DOI: 10.1016/j.dnarep.2021.103131 -
Critical Reviews in Biochemistry and... Apr 2017Cellular DNA replication is initiated through the action of multiprotein complexes that recognize replication start sites in the chromosome (termed origins) and... (Review)
Review
Cellular DNA replication is initiated through the action of multiprotein complexes that recognize replication start sites in the chromosome (termed origins) and facilitate duplex DNA melting within these regions. In a typical cell cycle, initiation occurs only once per origin and each round of replication is tightly coupled to cell division. To avoid aberrant origin firing and re-replication, eukaryotes tightly regulate two events in the initiation process: loading of the replicative helicase, MCM2-7, onto chromatin by the origin recognition complex (ORC), and subsequent activation of the helicase by its incorporation into a complex known as the CMG. Recent work has begun to reveal the details of an orchestrated and sequential exchange of initiation factors on DNA that give rise to a replication-competent complex, the replisome. Here, we review the molecular mechanisms that underpin eukaryotic DNA replication initiation - from selecting replication start sites to replicative helicase loading and activation - and describe how these events are often distinctly regulated across different eukaryotic model organisms.
Topics: Animals; Chromatin; DNA Replication; Enzyme Activation; Eukaryotic Cells; Humans; Minichromosome Maintenance Proteins; Origin Recognition Complex; Replication Origin
PubMed: 28094588
DOI: 10.1080/10409238.2016.1274717 -
The Enzymes 2016The initiation of chromosomal DNA replication starts at a replication origin, which in bacteria is a discrete locus that contains DNA sequence motifs recognized by an... (Review)
Review
The initiation of chromosomal DNA replication starts at a replication origin, which in bacteria is a discrete locus that contains DNA sequence motifs recognized by an initiator protein whose role is to assemble the replication fork machinery at this site. In bacteria with a single chromosome, DnaA is the initiator and is highly conserved in all bacteria. As an adenine nucleotide binding protein, DnaA bound to ATP is active in the assembly of a DnaA oligomer onto these sites. Other proteins modulate DnaA oligomerization via their interaction with the N-terminal region of DnaA. Following the DnaA-dependent unwinding of an AT-rich region within the replication origin, DnaA then mediates the binding of DnaB, the replicative DNA helicase, in a complex with DnaC to form an intermediate named the prepriming complex. In the formation of this intermediate, the helicase is loaded onto the unwound region within the replication origin. As DnaC bound to DnaB inhibits its activity as a DNA helicase, DnaC must dissociate to activate DnaB. Apparently, the interaction of DnaB with primase (DnaG) and primer formation leads to the release of DnaC from DnaB, which is coordinated with or followed by translocation of DnaB to the junction of the replication fork. There, DnaB is able to coordinate its activity as a DNA helicase with the cellular replicase, DNA polymerase III holoenzyme, which uses the primers made by primase for leading strand DNA synthesis.
Topics: Bacteria; Bacterial Proteins; DNA Helicases; DNA Replication; Replication Origin
PubMed: 27241926
DOI: 10.1016/bs.enz.2016.03.001 -
Biochemical Society Transactions Jun 2020DNA replication is a complex process that needs to be executed accurately before cell division in order to maintain genome integrity. DNA replication is divided into... (Review)
Review
DNA replication is a complex process that needs to be executed accurately before cell division in order to maintain genome integrity. DNA replication is divided into three main stages: initiation, elongation and termination. One of the key events during initiation is the assembly of the replicative helicase at origins of replication, and this mechanism has been very well described over the last decades. In the last six years however, researchers have also focused on deciphering the molecular mechanisms underlying the disassembly of the replicative helicase during termination. Similar to replisome assembly, the mechanism of replisome disassembly is strictly regulated and well conserved throughout evolution, although its complexity increases in higher eukaryotes. While budding yeast rely on just one pathway for replisome disassembly in S phase, higher eukaryotes evolved an additional mitotic pathway over and above the default S phase specific pathway. Moreover, replisome disassembly has been recently found to be a key event prior to the repair of certain DNA lesions, such as under-replicated DNA in mitosis and inter-strand cross-links (ICLs) in S phase. Although replisome disassembly in human cells has not been characterised yet, they possess all of the factors involved in these pathways in model organisms, and de-regulation of many of them are known to contribute to tumorigenesis and other pathological conditions.
Topics: Animals; Caenorhabditis elegans; Cell Cycle; Cell Cycle Proteins; Cell Survival; DNA; DNA Replication; Genome; Humans; Minichromosome Maintenance Complex Component 7; Mitosis; Neoplasms; Protein Interaction Mapping; Replication Origin; S Phase; Saccharomyces cerevisiae; Saccharomycetales; Ubiquitin; Ubiquitin-Protein Ligases; Ubiquitination; Xenopus laevis
PubMed: 32490508
DOI: 10.1042/BST20190363 -
Cold Spring Harbor Perspectives in... Oct 2013The onset of genomic DNA synthesis requires precise interactions of specialized initiator proteins with DNA at sites where the replication machinery can be loaded. These... (Review)
Review
The onset of genomic DNA synthesis requires precise interactions of specialized initiator proteins with DNA at sites where the replication machinery can be loaded. These sites, defined as replication origins, are found at a few unique locations in all of the prokaryotic chromosomes examined so far. However, replication origins are dispersed among tens of thousands of loci in metazoan chromosomes, thereby raising questions regarding the role of specific nucleotide sequences and chromatin environment in origin selection and the mechanisms used by initiators to recognize replication origins. Close examination of bacterial and archaeal replication origins reveals an array of DNA sequence motifs that position individual initiator protein molecules and promote initiator oligomerization on origin DNA. Conversely, the need for specific recognition sequences in eukaryotic replication origins is relaxed. In fact, the primary rule for origin selection appears to be flexibility, a feature that is modulated either by structural elements or by epigenetic mechanisms at least partly linked to the organization of the genome for gene expression.
Topics: Animals; Archaea; Bacteria; Binding Sites; Chromatin; DNA Replication; Drosophila; Models, Genetic; Origin Recognition Complex; Replication Origin; Saccharomyces cerevisiae; Yeasts
PubMed: 23838439
DOI: 10.1101/cshperspect.a010116 -
Molecular Cell Oct 2023Mitotic DNA synthesis (MiDAS) is an unusual form of DNA replication that occurs during mitosis. Initially, MiDAS was characterized as a process associated with... (Review)
Review
Mitotic DNA synthesis (MiDAS) is an unusual form of DNA replication that occurs during mitosis. Initially, MiDAS was characterized as a process associated with intrinsically unstable loci known as common fragile sites that occurs after cells experience DNA replication stress (RS). However, it is now believed to be a more widespread "salvage" mechanism that is called upon to complete the duplication of any under-replicated genomic region. Emerging data suggest that MiDAS is a DNA repair process potentially involving two or more pathways working in parallel or sequentially. In this review, we introduce the causes of RS, regions of the human genome known to be especially vulnerable to RS, and the strategies used to complete DNA replication outside of S phase. Additionally, because MiDAS is a prominent feature of aneuploid cancer cells, we will discuss how targeting MiDAS might potentially lead to improvements in cancer therapy.
Topics: Humans; S Phase; DNA Replication; DNA Repair; Mitosis; Virus Replication
PubMed: 37716351
DOI: 10.1016/j.molcel.2023.08.023 -
Annals of Botany May 2011The initiation of DNA replication is a very important and highly regulated step in the cell division cycle. It is of interest to compare different groups of eukaryotic... (Review)
Review
BACKGROUND
The initiation of DNA replication is a very important and highly regulated step in the cell division cycle. It is of interest to compare different groups of eukaryotic organisms (a) to identify the essential molecular events that occur in all eukaryotes, (b) to start to identify higher-level regulatory mechanisms that are specific to particular groups and (c) to gain insights into the evolution of initiation mechanisms.
SCOPE
This review features a wide-ranging literature survey covering replication origins, origin recognition and usage, modification of origin usage (especially in response to plant hormones), assembly of the pre-replication complex, loading of the replisome, genomics, and the likely origin of these mechanisms and proteins in Archaea.
CONCLUSIONS
In all eukaryotes, chromatin is organized for DNA replication as multiple replicons. In each replicon, replication is initiated at an origin. With the exception of those in budding yeast, replication origins, including the only one to be isolated so far from a plant, do not appear to embody a specific sequence; rather, they are AT-rich, with short tracts of locally bent DNA. The proteins involved in initiation are remarkably similar across the range of eukaryotes. Nevertheless, their activity may be modified by plant-specific mechanisms, including regulation by plant hormones. The molecular features of initiation are seen in a much simpler form in the Archaea. In particular, where eukaryotes possess a number of closely related proteins that form 'hetero-complexes' (such as the origin recognition complex and the MCM complex), archaeans typically possess one type of protein (e.g. one MCM) that forms a homo-complex. This suggests that several eukaryotic initiation proteins have evolved from archaeal ancestors by gene duplication and divergence.
Topics: DNA Replication; DNA, Plant; Evolution, Molecular; Models, Biological; Plant Growth Regulators; Replication Origin
PubMed: 21508040
DOI: 10.1093/aob/mcr075 -
Cold Spring Harbor Perspectives in... Mar 2013One of the fundamental challenges facing the cell is to accurately copy its genetic material to daughter cells. When this process goes awry, genomic instability ensues... (Review)
Review
One of the fundamental challenges facing the cell is to accurately copy its genetic material to daughter cells. When this process goes awry, genomic instability ensues in which genetic alterations ranging from nucleotide changes to chromosomal translocations and aneuploidy occur. Organisms have developed multiple mechanisms that can be classified into two major classes to ensure the fidelity of DNA replication. The first class includes mechanisms that prevent premature initiation of DNA replication and ensure that the genome is fully replicated once and only once during each division cycle. These include cyclin-dependent kinase (CDK)-dependent mechanisms and CDK-independent mechanisms. Although CDK-dependent mechanisms are largely conserved in eukaryotes, higher eukaryotes have evolved additional mechanisms that seem to play a larger role in preventing aberrant DNA replication and genome instability. The second class ensures that cells are able to respond to various cues that continuously threaten the integrity of the genome by initiating DNA-damage-dependent "checkpoints" and coordinating DNA damage repair mechanisms. Defects in the ability to safeguard against aberrant DNA replication and to respond to DNA damage contribute to genomic instability and the development of human malignancy. In this article, we summarize our current knowledge of how genomic instability arises, with a particular emphasis on how the DNA replication process can give rise to such instability.
Topics: Cell Cycle Checkpoints; Cell Cycle Proteins; DNA Damage; DNA Replication; Geminin; Genomic Instability; Humans; Minichromosome Maintenance Complex Component 2; Models, Biological; Neoplasms; Nuclear Proteins; Origin Recognition Complex; Ubiquitin-Protein Ligases
PubMed: 23335075
DOI: 10.1101/cshperspect.a012914