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PLoS Genetics Sep 2019In all kingdoms of life, DNA is used to encode hereditary information. Propagation of the genetic material between generations requires timely and accurate duplication... (Review)
Review
In all kingdoms of life, DNA is used to encode hereditary information. Propagation of the genetic material between generations requires timely and accurate duplication of DNA by semiconservative replication prior to cell division to ensure each daughter cell receives the full complement of chromosomes. DNA synthesis of daughter strands starts at discrete sites, termed replication origins, and proceeds in a bidirectional manner until all genomic DNA is replicated. Despite the fundamental nature of these events, organisms have evolved surprisingly divergent strategies that control replication onset. Here, we discuss commonalities and differences in replication origin organization and recognition in the three domains of life.
Topics: Biological Evolution; Cell Division; Chromosomes; DNA Replication; Evolution, Molecular; Replication Origin; Replicon
PubMed: 31513569
DOI: 10.1371/journal.pgen.1008320 -
Nature Reviews. Molecular Cell Biology Nov 2019The major pathways of DNA double-strand break (DSB) repair are crucial for maintaining genomic stability. However, if deployed in an inappropriate cellular context,... (Review)
Review
The major pathways of DNA double-strand break (DSB) repair are crucial for maintaining genomic stability. However, if deployed in an inappropriate cellular context, these same repair functions can mediate chromosome rearrangements that underlie various human diseases, ranging from developmental disorders to cancer. The two major mechanisms of DSB repair in mammalian cells are non-homologous end joining (NHEJ) and homologous recombination. In this Review, we consider DSB repair-pathway choice in somatic mammalian cells as a series of 'decision trees', and explore how defective pathway choice can lead to genomic instability. Stalled, collapsed or broken DNA replication forks present a distinctive challenge to the DSB repair system. Emerging evidence suggests that the 'rules' governing repair-pathway choice at stalled replication forks differ from those at replication-independent DSBs.
Topics: Animals; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Replication; Genomic Instability; Humans
PubMed: 31263220
DOI: 10.1038/s41580-019-0152-0 -
Nature Reviews. Molecular Cell Biology Jan 2022Cancer is a group of diseases in which cells divide continuously and excessively. Cell division is tightly regulated by multiple evolutionarily conserved cell cycle... (Review)
Review
Cancer is a group of diseases in which cells divide continuously and excessively. Cell division is tightly regulated by multiple evolutionarily conserved cell cycle control mechanisms, to ensure the production of two genetically identical cells. Cell cycle checkpoints operate as DNA surveillance mechanisms that prevent the accumulation and propagation of genetic errors during cell division. Checkpoints can delay cell cycle progression or, in response to irreparable DNA damage, induce cell cycle exit or cell death. Cancer-associated mutations that perturb cell cycle control allow continuous cell division chiefly by compromising the ability of cells to exit the cell cycle. Continuous rounds of division, however, create increased reliance on other cell cycle control mechanisms to prevent catastrophic levels of damage and maintain cell viability. New detailed insights into cell cycle control mechanisms and their role in cancer reveal how these dependencies can be best exploited in cancer treatment.
Topics: Animals; Cell Cycle Checkpoints; DNA Damage; DNA Replication; Humans; Neoplasms; Oncogenes; Spindle Apparatus
PubMed: 34508254
DOI: 10.1038/s41580-021-00404-3 -
Viruses Oct 2021DNA replication is an integral step in the herpes simplex virus type 1 (HSV-1) life cycle that is coordinated with the cellular DNA damage response, repair and... (Review)
Review
DNA replication is an integral step in the herpes simplex virus type 1 (HSV-1) life cycle that is coordinated with the cellular DNA damage response, repair and recombination of the viral genome, and viral gene transcription. HSV-1 encodes its own DNA replication machinery, including an origin binding protein (UL9), single-stranded DNA binding protein (ICP8), DNA polymerase (UL30), processivity factor (UL42), and a helicase/primase complex (UL5/UL8/UL52). In addition, HSV-1 utilizes a combination of accessory viral and cellular factors to coordinate viral DNA replication with other viral and cellular processes. The purpose of this review is to outline the roles of viral and cellular proteins in HSV-1 DNA replication and replication-coupled processes, and to highlight how HSV-1 may modify and adapt cellular proteins to facilitate productive infection.
Topics: DNA Helicases; DNA Primase; DNA Replication; DNA, Viral; DNA-Binding Proteins; DNA-Directed DNA Polymerase; Genome, Viral; Herpesvirus 1, Human; Humans; Viral Proteins; Virus Replication
PubMed: 34696446
DOI: 10.3390/v13102015 -
Annual Review of Biochemistry Jun 2022DNA replication in eukaryotic cells initiates from large numbers of sites called replication origins. Initiation of replication from these origins must be tightly... (Review)
Review
DNA replication in eukaryotic cells initiates from large numbers of sites called replication origins. Initiation of replication from these origins must be tightly controlled to ensure the entire genome is precisely duplicated in each cell cycle. This is accomplished through the regulation of the first two steps in replication: loading and activation of the replicative DNA helicase. Here we describe what is known about the mechanism and regulation of these two reactions from a genetic, biochemical, and structural perspective, focusing on recent progress using proteins from budding yeast.
Topics: Cell Cycle; DNA Replication; Eukaryota; Eukaryotic Cells; Replication Origin
PubMed: 35320688
DOI: 10.1146/annurev-biochem-072321-110228 -
Viruses Feb 2021Adenoviruses have served as a model for investigating viral-cell interactions and discovering different cellular processes, such as RNA splicing and DNA replication. In... (Review)
Review
Adenoviruses have served as a model for investigating viral-cell interactions and discovering different cellular processes, such as RNA splicing and DNA replication. In addition, the development and evaluation of adenoviruses as the viral vectors for vaccination and gene therapy has led to detailed investigations about adenovirus biology, including the structure and function of the adenovirus encoded proteins. While the determination of the structure and function of the viral capsid proteins in adenovirus biology has been the subject of numerous reports, the last few years have seen increased interest in elucidating the structure and function of the adenovirus core proteins. Here, we provide a review of research about the structure and function of the adenovirus core proteins in adenovirus biology.
Topics: Adenoviridae; Adenoviridae Infections; Animals; Capsid Proteins; DNA Replication; DNA, Viral; Humans; Viral Proteins; Virus Replication
PubMed: 33671079
DOI: 10.3390/v13030388 -
Genes Jul 2021Hydroxyurea (HU) is mostly referred to as an inhibitor of ribonucleotide reductase (RNR) and as the agent that is commonly used to arrest cells in the S-phase of the... (Review)
Review
Hydroxyurea (HU) is mostly referred to as an inhibitor of ribonucleotide reductase (RNR) and as the agent that is commonly used to arrest cells in the S-phase of the cycle by inducing replication stress. It is a well-known and widely used drug, one which has proved to be effective in treating chronic myeloproliferative disorders and which is considered a staple agent in sickle anemia therapy and-recently-a promising factor in preventing cognitive decline in Alzheimer's disease. The reversibility of HU-induced replication inhibition also makes it a common laboratory ingredient used to synchronize cell cycles. On the other hand, prolonged treatment or higher dosage of hydroxyurea causes cell death due to accumulation of DNA damage and oxidative stress. Hydroxyurea treatments are also still far from perfect and it has been suggested that it facilitates skin cancer progression. Also, recent studies have shown that hydroxyurea may affect a larger number of enzymes due to its less specific interaction mechanism, which may contribute to further as-yet unspecified factors affecting cell response. In this review, we examine the actual state of knowledge about hydroxyurea and the mechanisms behind its cytotoxic effects. The practical applications of the recent findings may prove to enhance the already existing use of the drug in new and promising ways.
Topics: Animals; DNA Replication; Humans; Hydroxyurea; Ribonucleotide Reductases; S Phase
PubMed: 34356112
DOI: 10.3390/genes12071096 -
Nucleic Acids Research Dec 2020Efficient S phase entry is essential for development, tissue repair, and immune defences. However, hyperactive or expedited S phase entry causes replication stress, DNA... (Review)
Review
Efficient S phase entry is essential for development, tissue repair, and immune defences. However, hyperactive or expedited S phase entry causes replication stress, DNA damage and oncogenesis, highlighting the need for strict regulation. Recent paradigm shifts and conflicting reports demonstrate the requirement for a discussion of the G1/S transition literature. Here, we review the recent studies, and propose a unified model for the S phase entry decision. In this model, competition between mitogen and DNA damage signalling over the course of the mother cell cycle constitutes the predominant control mechanism for S phase entry of daughter cells. Mitogens and DNA damage have distinct sensing periods, giving rise to three Commitment Points for S phase entry (CP1-3). S phase entry is mitogen-independent in the daughter G1 phase, but remains sensitive to DNA damage, such as single strand breaks, the most frequently-occurring lesions that uniquely threaten DNA replication. To control CP1-3, dedicated hubs integrate the antagonistic mitogenic and DNA damage signals, regulating the stoichiometric cyclin: CDK inhibitor ratio for ultrasensitive control of CDK4/6 and CDK2. This unified model for the G1/S cell cycle transition combines the findings of decades of study, and provides an updated foundation for cell cycle research.
Topics: Cell Cycle; Cell Cycle Checkpoints; Cell Division; DNA Damage; DNA Replication; G1 Phase; Humans; S Phase; Signal Transduction
PubMed: 33166394
DOI: 10.1093/nar/gkaa1002 -
Nature Reviews. Molecular Cell Biology Jun 2022Human topoisomerases comprise a family of six enzymes: two type IB (TOP1 and mitochondrial TOP1 (TOP1MT), two type IIA (TOP2A and TOP2B) and two type IA (TOP3A and... (Review)
Review
Human topoisomerases comprise a family of six enzymes: two type IB (TOP1 and mitochondrial TOP1 (TOP1MT), two type IIA (TOP2A and TOP2B) and two type IA (TOP3A and TOP3B) topoisomerases. In this Review, we discuss their biochemistry and their roles in transcription, DNA replication and chromatin remodelling, and highlight the recent progress made in understanding TOP3A and TOP3B. Because of recent advances in elucidating the high-order organization of the genome through chromatin loops and topologically associating domains (TADs), we integrate the functions of topoisomerases with genome organization. We also discuss the physiological and pathological formation of irreversible topoisomerase cleavage complexes (TOPccs) as they generate topoisomerase DNA-protein crosslinks (TOP-DPCs) coupled with DNA breaks. We discuss the expanding number of redundant pathways that repair TOP-DPCs, and the defects in those pathways, which are increasingly recognized as source of genomic damage leading to neurological diseases and cancer.
Topics: DNA Damage; DNA Replication; Genomic Instability; Humans; Mitochondria; Neoplasms
PubMed: 35228717
DOI: 10.1038/s41580-022-00452-3 -
Methods in Molecular Biology (Clifton,... 2020Gel electrophoresis of DNA is one of the most frequently used techniques in molecular biology. Typically, it is used in the following: the analysis of in vitro reactions...
Gel electrophoresis of DNA is one of the most frequently used techniques in molecular biology. Typically, it is used in the following: the analysis of in vitro reactions and purification of DNA fragments, analysis of PCR reactions, characterization of enzymes involved in DNA reactions, and sequencing. With some ingenuity gel electrophoresis of DNA is also used for the analysis of cellular biochemical reactions. For example, DNA breaks that accumulate in cells are analyzed by the comet assay and pulsed-field gel electrophoresis (PFGE). Furthermore, DNA replication intermediates are analyzed with two-dimensional (2D) gel electrophoresis. Moreover, several new methods for analyzing various chromosomal functions in cells have been developed. In this chapter, a brief introduction to these is given.
Topics: DNA; DNA Breaks; DNA Replication; Electrophoresis, Agar Gel; Electrophoresis, Gel, Pulsed-Field; Electrophoresis, Gel, Two-Dimensional
PubMed: 31989510
DOI: 10.1007/978-1-0716-0323-9_1