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Genes & Development Aug 2016For more than three decades, investigators have sought to identify the precise locations where DNA replication initiates in mammalian genomes. The development of... (Review)
Review
For more than three decades, investigators have sought to identify the precise locations where DNA replication initiates in mammalian genomes. The development of molecular and biochemical approaches to identify start sites of DNA replication (origins) based on the presence of defining and characteristic replication intermediates at specific loci led to the identification of only a handful of mammalian replication origins. The limited number of identified origins prevented a comprehensive and exhaustive search for conserved genomic features that were capable of specifying origins of DNA replication. More recently, the adaptation of origin-mapping assays to genome-wide approaches has led to the identification of tens of thousands of replication origins throughout mammalian genomes, providing an unprecedented opportunity to identify both genetic and epigenetic features that define and regulate their distribution and utilization. Here we summarize recent advances in our understanding of how primary sequence, chromatin environment, and nuclear architecture contribute to the dynamic selection and activation of replication origins across diverse cell types and developmental stages.
Topics: Animals; DNA Replication; Mammals; Replication Origin
PubMed: 27542827
DOI: 10.1101/gad.285114.116 -
Methods in Molecular Biology (Clifton,... 2009DNA replication is a complex mechanism that functions due to the co-ordinated interplay of several dozen protein factors. In the last few years, numerous studies... (Review)
Review
DNA replication is a complex mechanism that functions due to the co-ordinated interplay of several dozen protein factors. In the last few years, numerous studies suggested a tight implication of DNA replication factors in several DNA transaction events that maintain the integrity of the genome. Therefore, DNA replication fork proteins have also to be considered as part of a general process aiming at replicating and protecting the genome in order to allow the correct function of a cell and of its eventual daughter cells. This is illustrated by several DNA repair pathways such as base excision repair, nucleotide excision repair, double-strand break repair, and mismatch repair. Furthermore, several of the replication proteins have also been shown to be essential in sensing and transducing DNA damages through the checkpoint cascade pathways. This review will summarize the properties of DNA replication proteins that function exclusively at the replication fork.
Topics: DNA Damage; DNA Helicases; DNA Ligases; DNA Repair; DNA Replication; DNA-Binding Proteins; DNA-Directed DNA Polymerase; Models, Biological; Proliferating Cell Nuclear Antigen; Replication Origin; Replication Protein C
PubMed: 19563099
DOI: 10.1007/978-1-60327-815-7_2 -
Molecules (Basel, Switzerland) Sep 2019G-quadruplexes are four-stranded guanine-rich structures that have been demonstrated to occur across the genome in humans and other organisms. They provide regulatory... (Review)
Review
G-quadruplexes are four-stranded guanine-rich structures that have been demonstrated to occur across the genome in humans and other organisms. They provide regulatory functions during transcription, translation and immunoglobulin gene rearrangement, but there is also a large amount of evidence that they can present a potent barrier to the DNA replication machinery. This mini-review will summarize recent advances in understanding the many strategies nature has evolved to overcome G-quadruplex-mediated replication blockage, including removal of the structure by helicases or nucleases, or circumventing the deleterious effects on the genome through homologous recombination, alternative end-joining or synthesis re-priming. Paradoxically, G-quadruplexes have also recently been demonstrated to provide a positive role in stimulating the initiation of DNA replication. These recent studies have not only illuminated the many roles and consequences of G-quadruplexes, but have also provided fundamental insights into the general mechanisms of DNA replication and its links with genetic and epigenetic stability.
Topics: DNA Helicases; DNA Replication; Deoxyribonucleases; G-Quadruplexes; Humans
PubMed: 31546714
DOI: 10.3390/molecules24193439 -
Postepy Biochemii 2008DNA replication fidelity plays fundamental role in faithful transmission of genetic material during cell division and during transfer of genetic material from parents to... (Review)
Review
DNA replication fidelity plays fundamental role in faithful transmission of genetic material during cell division and during transfer of genetic material from parents to progeny. Replicative polymerases are the main guardian responsible for high replication fidelity of genomic DNA. DNA main replicative polymerases are also involved in many DNA repair processes. High fidelity of DNA replication is determined by correct nucleotide selectivity in polymerase active center, and exonucleolytic proofreading that removes mismatches from primer terminus. In this article we will focus on the mechanisms that are responsible for high fidelity of replications with the special emphasis on structural studies showing important conformational changes after substrate binding. We will also stress the importance of hydrogen bonding, base pair geometry, polymerase DNA interactions and the role of accessory proteins in replication fidelity.
Topics: Animals; Base Pair Mismatch; DNA Repair; DNA Replication; DNA-Directed DNA Polymerase; Humans; Hydrogen Bonding; Mutation
PubMed: 18610581
DOI: No ID Found -
Critical Reviews in Biochemistry and... Dec 2020Mammalian mitochondria contain multiple copies of a circular, double-stranded DNA genome (mtDNA) that codes for subunits of the oxidative phosphorylation machinery.... (Review)
Review
Mammalian mitochondria contain multiple copies of a circular, double-stranded DNA genome (mtDNA) that codes for subunits of the oxidative phosphorylation machinery. Mutations in mtDNA cause a number of rare, human disorders and are also associated with more common conditions, such as neurodegeneration and biological aging. In this review, we discuss our current understanding of mtDNA replication in mammalian cells and how this process is regulated. We also discuss how deletions can be formed during mtDNA replication.
Topics: Animals; DNA Helicases; DNA Replication; DNA, Mitochondrial; Humans; Mitochondria; Mitochondrial Proteins
PubMed: 32972254
DOI: 10.1080/10409238.2020.1818684 -
Annual Review of Biochemistry 1992
Review
Topics: Coliphages; DNA Replication; DNA-Directed DNA Polymerase; Escherichia coli; Models, Biological; Prokaryotic Cells
PubMed: 1497322
DOI: 10.1146/annurev.bi.61.070192.003325 -
Mutation Research. Reviews in Mutation... 2021DNA replication stress is a major source of DNA damage, including double-stranded breaks that promote DNA damage response (DDR) signaling. Inefficient repair of such... (Review)
Review
DNA replication stress is a major source of DNA damage, including double-stranded breaks that promote DNA damage response (DDR) signaling. Inefficient repair of such lesions can affect genome integrity. During DNA replication different factors act on chromatin remodeling in a coordinated way. While recent studies have highlighted individual molecular mechanisms of interaction, less is known about the orchestration of chromatin changes under replication stress. In this review we attempt to explore the complex relationship between DNA replication stress, DDR and genome integrity in mammalian cells, taking into account the role of chromatin disposition as an important modulator of DNA repair. Recent data on chromatin restoration and epigenetic re-establishment after DNA replication stress are reviewed.
Topics: Animals; Chromatin; Chromatin Assembly and Disassembly; DNA Damage; DNA Replication; Genomic Instability; Humans
PubMed: 34083038
DOI: 10.1016/j.mrrev.2020.108346 -
Biochimie Nov 2015Understanding how frequently spontaneous replication arrests occur and how archaea deal with these arrests are very interesting and challenging research topics. Here we... (Review)
Review
Understanding how frequently spontaneous replication arrests occur and how archaea deal with these arrests are very interesting and challenging research topics. Here we will described how genetic and imaging studies have revealed the central role of the archaeal helicase/nuclease Hef belonging to the XPF/MUS81/FANCM family of endonucleases in repair of arrested replication forks. Special focus will be on description of a recently developed combination of genetic and imaging tools to study the dynamic localization of a functional Hef::GFP (Green Fluorescent Protein) fusion protein in the living cells of halophilic archaea Haloferax volcanii. As Archaea provide an excellent and unique model for understanding how DNA replication is regulated to allow replication of a circular DNA molecule either from single or multiple replication origins, we will also summarize recent studies that have revealed peculiar features regarding DNA replication, particularly in halophilic archaea. We strongly believe that fundamental knowledge of our on-going studies will shed light on the evolutionary history of the DNA replication machinery and will help to establish general rules concerning replication restart and the key role of recombination proteins not only in bacteria, yeast and higher eukaryotes but also in archaea.
Topics: DNA Helicases; DNA Replication; Haloferax volcanii
PubMed: 26215377
DOI: 10.1016/j.biochi.2015.07.022 -
Seminars in Cancer Biology Feb 2024Accurate and complete DNA duplication is critical for maintaining genome integrity. Multiple mechanisms regulate when and where DNA replication takes place, to ensure... (Review)
Review
Accurate and complete DNA duplication is critical for maintaining genome integrity. Multiple mechanisms regulate when and where DNA replication takes place, to ensure that the entire genome is duplicated once and only once per cell cycle. Although the bulk of the genome is copied during the S phase of the cell cycle, increasing evidence suggests that parts of the genome are replicated in G2 or mitosis, in a last attempt to secure that daughter cells inherit an accurate copy of parental DNA. Remaining unreplicated gaps may be passed down to progeny and replicated in the next G1 or S phase. These findings challenge the long-established view that genome duplication occurs strictly during the S phase, bridging DNA replication to DNA repair and providing novel therapeutic strategies for cancer treatment.
Topics: Humans; S Phase; Cell Cycle; DNA Replication; Mitosis; DNA
PubMed: 38346544
DOI: 10.1016/j.semcancer.2024.02.002 -
Environmental and Molecular Mutagenesis Aug 2020Checkpoint kinase 2 (human CHEK2; murine Chk2) is a critical mediator of the DNA damage response and has established roles in DNA double strand break (DSB)-induced... (Review)
Review
Checkpoint kinase 2 (human CHEK2; murine Chk2) is a critical mediator of the DNA damage response and has established roles in DNA double strand break (DSB)-induced apoptosis and cell cycle arrest. DSBs may be invoked directly by ionizing radiation but may also arise indirectly from environmental exposures such as solar ultraviolet (UV) radiation. The primary forms of DNA damage induced by UV are DNA photolesions (such as cyclobutane pyrimidine dimers CPD and 6-4 photoproducts) which interfere with DNA synthesis and lead to DNA replication fork stalling. Persistently stalled and unresolved DNA replication forks can "collapse" to generate DSBs that induce signaling via Chk2 and its upstream activator the ataxia telangiectasia-mutated (ATM) protein kinase. This review focuses on recently defined roles of Chk2 in protecting against DNA replication-associated genotoxicity. Several DNA damage response factors such as Rad18, Nbs1 and Chk1 suppress stalling and collapse of DNA replication forks. Defects in the primary responders to DNA replication fork stalling lead to generation of DSB and reveal "back-up" roles for Chk2 in S-phase progression and genomic stability. In humans, there are numerous variants of the CHEK2 gene, including CHEK2*1100delC. Individuals with the CHEK2*1100delC germline alteration have an increased risk of developing breast cancer and malignant melanoma. DNA replication fork-stalling at estrogen-DNA adducts and UV-induced photolesions are implicated in the etiology of breast cancer and melanoma, respectively. It is likely therefore that the Chk2/CHEK2-deficiency is associated with elevated risk for tumorigenesis caused by replication-associated genotoxicities that are exacerbated by environmental genotoxins and intrinsic DNA-damaging agents.
Topics: Animals; Carcinogenesis; Checkpoint Kinase 2; DNA Damage; DNA Replication; Environmental Exposure; Humans; Neoplasms
PubMed: 32578892
DOI: 10.1002/em.22397