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Special Issue "DNA Replication Controls"

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics".

Deadline for manuscript submissions: closed (31 October 2016)

Special Issue Editor

Guest Editor
Dr. Eishi Noguchi

Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA
Website | E-Mail
Interests: DNA replication; DNA repair; genomic instability; cancer; aging

Special Issue Information

Dear Colleagues,

The conditions for DNA replication are not ideal, owing to endogenous and exogenous replication stresses that lead to arrest of the replication fork. Arrested forks are among the most serious threats to genomic integrity because they can break or rearrange, leading to genomic instability. Thus, it is important to understand the cellular programs that preserve genomic integrity during DNA replication. Indeed, the most common cancer therapies use agents that block DNA replication or cause DNA damage during replication. Thus, without a precise understanding of the DNA replication program, development of anticancer therapeutics is limited.

In this Special Issue, we welcome reviews, new methods, and original articles covering many aspects of DNA replication controls. These include, but not limited to, regulation of the replisome and its components, DNA replication checkpoints, S-phase stress responses, replication of difficult-to-replication sites, replication of specific genomic loci (such as telomeres and rDNA), translesion synthesis, DNA repair during DNA replication, and other cellular processes that are coordinated with DNA replication. We look forward to your contributions.

Dr. Eishi Noguchi
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • DNA replication
  • DNA repair
  • genomic instability
  • replication checkpoint
  • telomere replication
  • replisome
  • replication stress
  • DNA polymerase
  • DNA helicase
  • translesion synthesis

Published Papers (32 papers)

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Research

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Open AccessArticle Error-Free Bypass of 7,8-dihydro-8-oxo-2′-deoxyguanosine by DNA Polymerase of Pseudomonas aeruginosa Phage PaP1
Genes 2017, 8(1), 18; doi:10.3390/genes8010018
Received: 21 November 2016 / Revised: 26 December 2016 / Accepted: 30 December 2016 / Published: 6 January 2017
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Abstract
As one of the most common forms of oxidative DNA damage, 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-oxoG) generally leads to G:C to T:A mutagenesis. To study DNA replication encountering 8-oxoG by the sole DNA polymerase (Gp90) of Pseudomonas aeruginosa phage PaP1, we performed steady-state and pre-steady-state kinetic
[...] Read more.
As one of the most common forms of oxidative DNA damage, 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-oxoG) generally leads to G:C to T:A mutagenesis. To study DNA replication encountering 8-oxoG by the sole DNA polymerase (Gp90) of Pseudomonas aeruginosa phage PaP1, we performed steady-state and pre-steady-state kinetic analyses of nucleotide incorporation opposite 8-oxoG by Gp90 D234A that lacks exonuclease activities on ssDNA and dsDNA substrates. Gp90 D234A could bypass 8-oxoG in an error-free manner, preferentially incorporate dCTP opposite 8-oxoG, and yield similar misincorporation frequency to unmodified G. Gp90 D234A could extend beyond C:8-oxoG or A:8-oxoG base pairs with the same efficiency. dCTP incorporation opposite G and dCTP or dATP incorporation opposite 8-oxoG showed fast burst phases. The burst of incorporation efficiency (kpol/Kd,dNTP) is decreased as dCTP:G > dCTP:8-oxoG > dATP:8-oxoG. The presence of 8-oxoG in DNA does not affect its binding to Gp90 D234A in a binary complex but it does affect it in a ternary complex with dNTP and Mg2+, and dATP misincorporation opposite 8-oxoG further weakens the binding of Gp90 D234A to DNA. This study reveals Gp90 D234A can bypass 8-oxoG in an error-free manner, providing further understanding in DNA replication encountering oxidation lesion for P.aeruginosa phage PaP1. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Review

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Open AccessReview Anatomy of Mammalian Replication Domains
Genes 2017, 8(4), 110; doi:10.3390/genes8040110
Received: 8 December 2016 / Revised: 22 March 2017 / Accepted: 24 March 2017 / Published: 28 March 2017
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Abstract
Genetic information is faithfully copied by DNA replication through many rounds of cell division. In mammals, DNA is replicated in Mb-sized chromosomal units called “replication domains.” While genome-wide maps in multiple cell types and disease states have uncovered both dynamic and static properties
[...] Read more.
Genetic information is faithfully copied by DNA replication through many rounds of cell division. In mammals, DNA is replicated in Mb-sized chromosomal units called “replication domains.” While genome-wide maps in multiple cell types and disease states have uncovered both dynamic and static properties of replication domains, we are still in the process of understanding the mechanisms that give rise to these properties. A better understanding of the molecular basis of replication domain regulation will bring new insights into chromosome structure and function. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview DNA Replication Origins and Fork Progression at Mammalian Telomeres
Genes 2017, 8(4), 112; doi:10.3390/genes8040112
Received: 7 February 2017 / Revised: 23 March 2017 / Accepted: 24 March 2017 / Published: 28 March 2017
PDF Full-text (1066 KB)
Abstract
Telomeres are essential chromosomal regions that prevent critical shortening of linear chromosomes and genomic instability in eukaryotic cells. The bulk of telomeric DNA is replicated by semi-conservative DNA replication in the same way as the rest of the genome. However, recent findings revealed
[...] Read more.
Telomeres are essential chromosomal regions that prevent critical shortening of linear chromosomes and genomic instability in eukaryotic cells. The bulk of telomeric DNA is replicated by semi-conservative DNA replication in the same way as the rest of the genome. However, recent findings revealed that replication of telomeric repeats is a potential cause of chromosomal instability, because DNA replication through telomeres is challenged by the repetitive telomeric sequences and specific structures that hamper the replication fork. In this review, we summarize current understanding of the mechanisms by which telomeres are faithfully and safely replicated in mammalian cells. Various telomere-associated proteins ensure efficient telomere replication at different steps, such as licensing of replication origins, passage of replication forks, proper fork restart after replication stress, and dissolution of post-replicative structures. In particular, shelterin proteins have central roles in the control of telomere replication. Through physical interactions, accessory proteins are recruited to maintain telomere integrity during DNA replication. Dormant replication origins and/or homology-directed repair may rescue inappropriate fork stalling or collapse that can cause defects in telomere structure and functions. Full article
(This article belongs to the Special Issue DNA Replication Controls)
Open AccessReview Roles of CDK and DDK in Genome Duplication and Maintenance: Meiotic Singularities
Genes 2017, 8(3), 105; doi:10.3390/genes8030105
Received: 21 February 2017 / Revised: 13 March 2017 / Accepted: 14 March 2017 / Published: 20 March 2017
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Abstract
Cells reproduce using two types of divisions: mitosis, which generates two daughter cells each with the same genomic content as the mother cell, and meiosis, which reduces the number of chromosomes of the parent cell by half and gives rise to four gametes.
[...] Read more.
Cells reproduce using two types of divisions: mitosis, which generates two daughter cells each with the same genomic content as the mother cell, and meiosis, which reduces the number of chromosomes of the parent cell by half and gives rise to four gametes. The mechanisms that promote the proper progression of the mitotic and meiotic cycles are highly conserved and controlled. They require the activities of two types of serine-threonine kinases, the cyclin-dependent kinases (CDKs) and the Dbf4-dependent kinase (DDK). CDK and DDK are essential for genome duplication and maintenance in both mitotic and meiotic divisions. In this review, we aim to highlight how these kinases cooperate to orchestrate diverse processes during cellular reproduction, focusing on meiosis-specific adaptions of their regulation and functions in DNA metabolism.
Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview Regulation of DNA Replication through Natural  Impediments in the Eukaryotic Genome
Genes 2017, 8(3), 98; doi:10.3390/genes8030098
Received: 10 December 2016 / Accepted: 3 March 2017 / Published: 7 March 2017
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Abstract
All living organisms need to duplicate their genetic information while protecting it from unwanted mutations, which can lead to genetic disorders and cancer development. Inaccuracies during DNA replication are the major cause of genomic instability, as replication forks are prone to stalling and
[...] Read more.
All living organisms need to duplicate their genetic information while protecting it from unwanted mutations, which can lead to genetic disorders and cancer development. Inaccuracies during DNA replication are the major cause of genomic instability, as replication forks are prone to stalling and collapse, resulting in DNA damage. The presence of exogenous DNA damaging agents as well as endogenous difficult‐to‐replicate DNA regions containing DNA–protein complexes, repetitive DNA, secondary DNA structures, or transcribing RNA polymerases, increases the risk of genomic instability and thus threatens cell survival. Therefore, understanding the cellular mechanisms required to preserve the genetic information during S phase is of paramount importance. In this review, we will discuss our current understanding of how cells cope with these natural impediments in order to prevent DNA damage and genomic instability during DNA replication. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview The Role of the Transcriptional Response to DNA Replication Stress
Genes 2017, 8(3), 92; doi:10.3390/genes8030092
Received: 20 January 2017 / Revised: 20 February 2017 / Accepted: 23 February 2017 / Published: 2 March 2017
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Abstract
During DNA replication many factors can result in DNA replication stress. The DNA replication stress checkpoint prevents the accumulation of replication stress-induced DNA damage and the potential ensuing genome instability. A critical role for post-translational modifications, such as phosphorylation, in the replication stress
[...] Read more.
During DNA replication many factors can result in DNA replication stress. The DNA replication stress checkpoint prevents the accumulation of replication stress-induced DNA damage and the potential ensuing genome instability. A critical role for post-translational modifications, such as phosphorylation, in the replication stress checkpoint response has been well established. However, recent work has revealed an important role for transcription in the cellular response to DNA replication stress. In this review, we will provide an overview of current knowledge of the cellular response to DNA replication stress with a specific focus on the DNA replication stress checkpoint transcriptional response and its role in the prevention of replication stress-induced DNA damage. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview Mcm10: A Dynamic Scaffold at Eukaryotic Replication Forks
Genes 2017, 8(2), 73; doi:10.3390/genes8020073
Received: 15 December 2016 / Revised: 9 February 2017 / Accepted: 9 February 2017 / Published: 17 February 2017
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Abstract
To complete the duplication of large genomes efficiently, mechanisms have evolved that coordinate DNA unwinding with DNA synthesis and provide quality control measures prior to cell division. Minichromosome maintenance protein 10 (Mcm10) is a conserved component of the eukaryotic replisome that contributes to
[...] Read more.
To complete the duplication of large genomes efficiently, mechanisms have evolved that coordinate DNA unwinding with DNA synthesis and provide quality control measures prior to cell division. Minichromosome maintenance protein 10 (Mcm10) is a conserved component of the eukaryotic replisome that contributes to this process in multiple ways. Mcm10 promotes the initiation of DNA replication through direct interactions with the cell division cycle 45 (Cdc45)-minichromosome maintenance complex proteins 2-7 (Mcm2-7)-go-ichi-ni-san GINS complex proteins, as well as single- and double-stranded DNA. After origin firing, Mcm10 controls replication fork stability to support elongation, primarily facilitating Okazaki fragment synthesis through recruitment of DNA polymerase-α and proliferating cell nuclear antigen. Based on its multivalent properties, Mcm10 serves as an essential scaffold to promote DNA replication and guard against replication stress. Under pathological conditions, Mcm10 is often dysregulated. Genetic amplification and/or overexpression of MCM10 are common in cancer, and can serve as a strong prognostic marker of poor survival. These findings are compatible with a heightened requirement for Mcm10 in transformed cells to overcome limitations for DNA replication dictated by altered cell cycle control. In this review, we highlight advances in our understanding of when, where and how Mcm10 functions within the replisome to protect against barriers that cause incomplete replication. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview The Intra-S Checkpoint Responses to DNA Damage
Genes 2017, 8(2), 74; doi:10.3390/genes8020074
Received: 7 January 2017 / Revised: 8 February 2017 / Accepted: 8 February 2017 / Published: 17 February 2017
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Abstract
Faithful duplication of the genome is a challenge because DNA is susceptible to damage by a number of intrinsic and extrinsic genotoxins, such as free radicals and UV light. Cells activate the intra-S checkpoint in response to damage during S phase to protect
[...] Read more.
Faithful duplication of the genome is a challenge because DNA is susceptible to damage by a number of intrinsic and extrinsic genotoxins, such as free radicals and UV light. Cells activate the intra-S checkpoint in response to damage during S phase to protect genomic integrity and ensure replication fidelity. The checkpoint prevents genomic instability mainly by regulating origin firing, fork progression, and transcription of G1/S genes in response to DNA damage. Several studies hint that regulation of forks is perhaps the most critical function of the intra-S checkpoint. However, the exact role of the checkpoint at replication forks has remained elusive and controversial. Is the checkpoint required for fork stability, or fork restart, or to prevent fork reversal or fork collapse, or activate repair at replication forks? What are the factors that the checkpoint targets at stalled replication forks? In this review, we will discuss the various pathways activated by the intra-S checkpoint in response to damage to prevent genomic instability. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview Mechanisms of Post-Replication DNA Repair
Genes 2017, 8(2), 64; doi:10.3390/genes8020064
Received: 5 December 2016 / Accepted: 3 February 2017 / Published: 8 February 2017
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Abstract
Accurate DNA replication is crucial for cell survival and the maintenance of genome stability. Cells have developed mechanisms to cope with the frequent genotoxic injuries that arise from both endogenous and environmental sources. Lesions encountered during DNA replication are often tolerated by post-replication
[...] Read more.
Accurate DNA replication is crucial for cell survival and the maintenance of genome stability. Cells have developed mechanisms to cope with the frequent genotoxic injuries that arise from both endogenous and environmental sources. Lesions encountered during DNA replication are often tolerated by post-replication repair mechanisms that prevent replication fork collapse and avert the formation of DNA double strand breaks. There are two predominant post-replication repair pathways, trans-lesion synthesis (TLS) and template switching (TS). TLS is a DNA damage-tolerant and low-fidelity mode of DNA synthesis that utilizes specialized ‘Y-family’ DNA polymerases to replicate damaged templates. TS, however, is an error-free ‘DNA damage avoidance’ mode of DNA synthesis that uses a newly synthesized sister chromatid as a template in lieu of the damaged parent strand. Both TLS and TS pathways are tightly controlled signaling cascades that integrate DNA synthesis with the overall DNA damage response and are thus crucial for genome stability. This review will cover the current knowledge of the primary mediators of post-replication repair and how they are regulated in the cell. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview Elaborated Action of the Human Primosome
Genes 2017, 8(2), 62; doi:10.3390/genes8020062
Received: 1 December 2016 / Accepted: 4 February 2017 / Published: 8 February 2017
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Abstract
The human primosome is a 340-kilodalton complex of primase (DNA-dependent RNA polymerase) and DNA polymerase α, which initiates genome replication by synthesizing chimeric RNA-DNA primers for DNA polymerases δ and ϵ. Accumulated biochemical and structural data reveal the complex mechanism of concerted primer
[...] Read more.
The human primosome is a 340-kilodalton complex of primase (DNA-dependent RNA polymerase) and DNA polymerase α, which initiates genome replication by synthesizing chimeric RNA-DNA primers for DNA polymerases δ and ϵ. Accumulated biochemical and structural data reveal the complex mechanism of concerted primer synthesis by two catalytic centers. First, primase generates an RNA primer through three steps: initiation, consisting of dinucleotide synthesis from two nucleotide triphosphates; elongation, resulting in dinucleotide extension; and termination, owing to primase inhibition by a mature 9-mer primer. Then Polα, which works equally well on DNA:RNA and DNA:DNA double helices, intramolecularly catches the template primed by a 9mer RNA and extends the primer with dNTPs. All primosome transactions are highly coordinated by autoregulation through the alternating activation/inhibition of the catalytic centers. This coordination is mediated by the small C-terminal domain of the primase accessory subunit, which forms a tight complex with the template:primer, shuttles between the primase and DNA polymerase active sites, and determines their access to the substrate. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview Solving the Telomere Replication Problem
Genes 2017, 8(2), 55; doi:10.3390/genes8020055
Received: 2 November 2016 / Accepted: 23 January 2017 / Published: 31 January 2017
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Abstract
Telomeres are complex nucleoprotein structures that protect the extremities of linear chromosomes. Telomere replication is a major challenge because many obstacles to the progression of the replication fork are concentrated at the ends of the chromosomes. This is known as the telomere replication
[...] Read more.
Telomeres are complex nucleoprotein structures that protect the extremities of linear chromosomes. Telomere replication is a major challenge because many obstacles to the progression of the replication fork are concentrated at the ends of the chromosomes. This is known as the telomere replication problem. In this article, different and new aspects of telomere replication, that can threaten the integrity of telomeres, will be reviewed. In particular, we will focus on the functions of shelterin and the replisome for the preservation of telomere integrity Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview A Critical Balance: dNTPs and the Maintenance of Genome Stability
Genes 2017, 8(2), 57; doi:10.3390/genes8020057
Received: 6 December 2016 / Accepted: 24 January 2017 / Published: 31 January 2017
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Abstract
A crucial factor in maintaining genome stability is establishing deoxynucleoside triphosphate (dNTP) levels within a range that is optimal for chromosomal replication. Since DNA replication is relevant to a wide range of other chromosomal activities, these may all be directly or indirectly affected
[...] Read more.
A crucial factor in maintaining genome stability is establishing deoxynucleoside triphosphate (dNTP) levels within a range that is optimal for chromosomal replication. Since DNA replication is relevant to a wide range of other chromosomal activities, these may all be directly or indirectly affected when dNTP concentrations deviate from a physiologically normal range. The importance of understanding these consequences is relevant to genetic disorders that disturb dNTP levels, and strategies that inhibit dNTP synthesis in cancer chemotherapy and for treatment of other disorders. We review here how abnormal dNTP levels affect DNA replication and discuss the consequences for genome stability. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview Diversity of DNA Replication in the Archaea
Genes 2017, 8(2), 56; doi:10.3390/genes8020056
Received: 29 November 2016 / Accepted: 20 January 2017 / Published: 31 January 2017
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Abstract
DNA replication is arguably the most fundamental biological process. On account of their shared evolutionary ancestry, the replication machinery found in archaea is similar to that found in eukaryotes. DNA replication is initiated at origins and is highly conserved in eukaryotes, but our
[...] Read more.
DNA replication is arguably the most fundamental biological process. On account of their shared evolutionary ancestry, the replication machinery found in archaea is similar to that found in eukaryotes. DNA replication is initiated at origins and is highly conserved in eukaryotes, but our limited understanding of archaea has uncovered a wide diversity of replication initiation mechanisms. Archaeal origins are sequence‐based, as in bacteria, but are bound by initiator proteins that share homology with the eukaryotic origin recognition complex subunit Orc1 and helicase loader Cdc6). Unlike bacteria, archaea may have multiple origins per chromosome and multiple Orc1/Cdc6 initiator proteins. There is no consensus on how these archaeal origins are recognised— some are bound by a single Orc1/Cdc6 protein while others require a multi‐ Orc1/Cdc6 complex. Many archaeal genomes consist of multiple parts—the main chromosome plus several megaplasmids—and in polyploid species these parts are present in multiple copies. This poses a challenge to the regulation of DNA replication. However, one archaeal species (Haloferax volcanii) can survive without replication origins; instead, it uses homologous recombination as an alternative mechanism of initiation. This diversity in DNA replication initiation is all the more remarkable for having been discovered in only three groups of archaea where in vivo studies are possible. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview Non‐Canonical Replication Initiation: You’re Fired!
Genes 2017, 8(2), 54; doi:10.3390/genes8020054
Received: 10 November 2016 / Accepted: 19 January 2017 / Published: 27 January 2017
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Abstract
The division of prokaryotic and eukaryotic cells produces two cells that inherit a perfect copy of the genetic material originally derived from the mother cell. The initiation of canonical DNA replication must be coordinated to the cell cycle to ensure the accuracy of
[...] Read more.
The division of prokaryotic and eukaryotic cells produces two cells that inherit a perfect copy of the genetic material originally derived from the mother cell. The initiation of canonical DNA replication must be coordinated to the cell cycle to ensure the accuracy of genome duplication. Controlled replication initiation depends on a complex interplay of cis‐acting DNA sequences, the so‐called origins of replication (ori), with trans‐acting factors involved in the onset of DNA synthesis. The interplay of cis‐acting elements and trans‐acting factors ensures that cells initiate replication at sequence‐specific sites only once, and in a timely order, to avoid chromosomal endoreplication. However, chromosome breakage and excessive RNA:DNA hybrid formation can cause breakinduced (BIR) or transcription‐initiated replication (TIR), respectively. These non‐canonical replication events are expected to affect eukaryotic genome function and maintenance, and could be important for genome evolution and disease development. In this review, we describe the difference between canonical and non‐canonical DNA replication, and focus on mechanistic differences and common features between BIR and TIR. Finally, we discuss open issues on the factors and molecular mechanisms involved in TIR. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview Control of Genome Integrity by RFC Complexes; Conductors of PCNA Loading onto and Unloading from Chromatin during DNA Replication
Genes 2017, 8(2), 52; doi:10.3390/genes8020052
Received: 28 November 2016 / Revised: 19 January 2017 / Accepted: 21 January 2017 / Published: 26 January 2017
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Abstract
During cell division, genome integrity is maintained by faithful DNA replication during S phase, followed by accurate segregation in mitosis. Many DNA metabolic events linked with DNA replication are also regulated throughout the cell cycle. In eukaryotes, the DNA sliding clamp, proliferating cell
[...] Read more.
During cell division, genome integrity is maintained by faithful DNA replication during S phase, followed by accurate segregation in mitosis. Many DNA metabolic events linked with DNA replication are also regulated throughout the cell cycle. In eukaryotes, the DNA sliding clamp, proliferating cell nuclear antigen (PCNA), acts on chromatin as a processivity factor for DNA polymerases. Since its discovery, many other PCNA binding partners have been identified that function during DNA replication, repair, recombination, chromatin remodeling, cohesion, and proteolysis in cell-cycle progression. PCNA not only recruits the proteins involved in such events, but it also actively controls their function as chromatin assembles. Therefore, control of PCNA-loading onto chromatin is fundamental for various replication-coupled reactions. PCNA is loaded onto chromatin by PCNA-loading replication factor C (RFC) complexes. Both RFC1-RFC and Ctf18-RFC fundamentally function as PCNA loaders. On the other hand, after DNA synthesis, PCNA must be removed from chromatin by Elg1-RFC. Functional defects in RFC complexes lead to chromosomal abnormalities. In this review, we summarize the structural and functional relationships among RFC complexes, and describe how the regulation of PCNA loading/unloading by RFC complexes contributes to maintaining genome integrity. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview Links between DNA Replication, Stem Cells and Cancer
Genes 2017, 8(2), 45; doi:10.3390/genes8020045
Received: 20 November 2016 / Revised: 2 January 2017 / Accepted: 12 January 2017 / Published: 25 January 2017
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Abstract
Cancers can be categorized into two groups: those whose frequency increases with age, and those resulting from errors during mammalian development. The first group is linked to DNA replication through the accumulation of genetic mutations that occur during proliferation of developmentally acquired stem
[...] Read more.
Cancers can be categorized into two groups: those whose frequency increases with age, and those resulting from errors during mammalian development. The first group is linked to DNA replication through the accumulation of genetic mutations that occur during proliferation of developmentally acquired stem cells that give rise to and maintain tissues and organs. These mutations, which result from DNA replication errors as well as environmental insults, fall into two categories; cancer driver mutations that initiate carcinogenesis and genome destabilizing mutations that promote aneuploidy through excess genome duplication and chromatid missegregation. Increased genome instability results in accelerated clonal evolution leading to the appearance of more aggressive clones with increased drug resistance. The second group of cancers, termed germ cell neoplasia, results from the mislocation of pluripotent stem cells during early development. During normal development, pluripotent stem cells that originate in early embryos give rise to all of the cell lineages in the embryo and adult, but when they mislocate to ectopic sites, they produce tumors. Remarkably, pluripotent stem cells, like many cancer cells, depend on the Geminin protein to prevent excess DNA replication from triggering DNA damage-dependent apoptosis. This link between the control of DNA replication during early development and germ cell neoplasia reveals Geminin as a potential chemotherapeutic target in the eradication of cancer progenitor cells. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview Regulation of Replication Fork Advance and Stability by Nucleosome Assembly
Genes 2017, 8(2), 49; doi:10.3390/genes8020049
Received: 25 November 2016 / Revised: 4 January 2017 / Accepted: 16 January 2017 / Published: 24 January 2017
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Abstract
The advance of replication forks to duplicate chromosomes in dividing cells requires the disassembly of nucleosomes ahead of the fork and the rapid assembly of parental and de novo histones at the newly synthesized strands behind the fork. Replication-coupled chromatin assembly provides a
[...] Read more.
The advance of replication forks to duplicate chromosomes in dividing cells requires the disassembly of nucleosomes ahead of the fork and the rapid assembly of parental and de novo histones at the newly synthesized strands behind the fork. Replication-coupled chromatin assembly provides a unique opportunity to regulate fork advance and stability. Through post-translational histone modifications and tightly regulated physical and genetic interactions between chromatin assembly factors and replisome components, chromatin assembly: (1) controls the rate of DNA synthesis and adjusts it to histone availability; (2) provides a mechanism to protect the integrity of the advancing fork; and (3) regulates the mechanisms of DNA damage tolerance in response to replication-blocking lesions. Uncoupling DNA synthesis from nucleosome assembly has deleterious effects on genome integrity and cell cycle progression and is linked to genetic diseases, cancer, and aging. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview Risks at the DNA Replication Fork: Effects upon Carcinogenesis and Tumor Heterogeneity
Genes 2017, 8(1), 46; doi:10.3390/genes8010046
Received: 6 December 2016 / Revised: 9 January 2017 / Accepted: 17 January 2017 / Published: 22 January 2017
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Abstract
The ability of all organisms to copy their genetic information via DNA replication is a prerequisite for cell division and a biological imperative of life. In multicellular organisms, however, mutations arising from DNA replication errors in the germline and somatic cells are the
[...] Read more.
The ability of all organisms to copy their genetic information via DNA replication is a prerequisite for cell division and a biological imperative of life. In multicellular organisms, however, mutations arising from DNA replication errors in the germline and somatic cells are the basis of genetic diseases and cancer, respectively. Within human tumors, replication errors additionally contribute to mutator phenotypes and tumor heterogeneity, which are major confounding factors for cancer therapeutics. Successful DNA replication involves the coordination of many large-scale, complex cellular processes. In this review, we focus on the roles that defects in enzymes that normally act at the replication fork and dysregulation of enzymes that inappropriately damage single-stranded DNA at the fork play in causing mutations that contribute to carcinogenesis. We focus on tumor data and experimental evidence that error-prone variants of replicative polymerases promote carcinogenesis and on research indicating that the primary target mutated by APOBEC (apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like) cytidine deaminases is ssDNA present at the replication fork. Furthermore, we discuss evidence from model systems that indicate replication stress and other cancer-associated metabolic changes may modulate mutagenic enzymatic activities at the replication fork. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview Regulation of DNA Replication in Early Embryonic Cleavages
Genes 2017, 8(1), 42; doi:10.3390/genes8010042
Received: 25 November 2016 / Revised: 6 January 2017 / Accepted: 11 January 2017 / Published: 19 January 2017
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Abstract
Early embryonic cleavages are characterized by short and highly synchronous cell cycles made of alternating S- and M-phases with virtually absent gap phases. In this contracted cell cycle, the duration of DNA synthesis can be extraordinarily short. Depending on the organism, the whole
[...] Read more.
Early embryonic cleavages are characterized by short and highly synchronous cell cycles made of alternating S- and M-phases with virtually absent gap phases. In this contracted cell cycle, the duration of DNA synthesis can be extraordinarily short. Depending on the organism, the whole genome of an embryo is replicated at a speed that is between 20 to 60 times faster than that of a somatic cell. Because transcription in the early embryo is repressed, DNA synthesis relies on a large stockpile of maternally supplied proteins stored in the egg representing most, if not all, cellular genes. In addition, in early embryonic cell cycles, both replication and DNA damage checkpoints are inefficient. In this article, we will review current knowledge on how DNA synthesis is regulated in early embryos and discuss possible consequences of replicating chromosomes with little or no quality control. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview Centromere Stability: The Replication Connection
Genes 2017, 8(1), 37; doi:10.3390/genes8010037
Received: 19 December 2016 / Revised: 10 January 2017 / Accepted: 12 January 2017 / Published: 18 January 2017
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Abstract
The fission yeast centromere, which is similar to metazoan centromeres, contains highly repetitive pericentromere sequences that are assembled into heterochromatin. This is required for the recruitment of cohesin and proper chromosome segregation. Surprisingly, the pericentromere replicates early in the S phase. Loss of
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The fission yeast centromere, which is similar to metazoan centromeres, contains highly repetitive pericentromere sequences that are assembled into heterochromatin. This is required for the recruitment of cohesin and proper chromosome segregation. Surprisingly, the pericentromere replicates early in the S phase. Loss of heterochromatin causes this domain to become very sensitive to replication fork defects, leading to gross chromosome rearrangements. This review examines the interplay between components of DNA replication, heterochromatin assembly, and cohesin dynamics that ensures maintenance of genome stability and proper chromosome segregation. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview Origin DNA Melting—An Essential Process with Divergent Mechanisms
Genes 2017, 8(1), 26; doi:10.3390/genes8010026
Received: 21 November 2016 / Revised: 27 December 2016 / Accepted: 3 January 2017 / Published: 11 January 2017
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Abstract
Origin DNA melting is an essential process in the various domains of life. The replication fork helicase unwinds DNA ahead of the replication fork, providing single-stranded DNA templates for the replicative polymerases. The replication fork helicase is a ring shaped-assembly that unwinds DNA
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Origin DNA melting is an essential process in the various domains of life. The replication fork helicase unwinds DNA ahead of the replication fork, providing single-stranded DNA templates for the replicative polymerases. The replication fork helicase is a ring shaped-assembly that unwinds DNA by a steric exclusion mechanism in most DNA replication systems. While one strand of DNA passes through the central channel of the helicase ring, the second DNA strand is excluded from the central channel. Thus, the origin, or initiation site for DNA replication, must melt during the initiation of DNA replication to allow for the helicase to surround a single-DNA strand. While this process is largely understood for bacteria and eukaryotic viruses, less is known about how origin DNA is melted at eukaryotic cellular origins. This review describes the current state of knowledge of how genomic DNA is melted at a replication origin in bacteria and eukaryotes. We propose that although the process of origin melting is essential for the various domains of life, the mechanism for origin melting may be quite different among the different DNA replication initiation systems. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview Control of Initiation of DNA Replication in Bacillus subtilis and Escherichia coli
Genes 2017, 8(1), 22; doi:10.3390/genes8010022
Received: 12 November 2016 / Revised: 16 December 2016 / Accepted: 20 December 2016 / Published: 10 January 2017
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Abstract
Initiation of DNA Replication is tightly regulated in all cells since imbalances in chromosomal copy number are deleterious and often lethal. In bacteria such as Bacillus subtilis and Escherichia coli, at the point of cytokinesis, there must be two complete copies of
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Initiation of DNA Replication is tightly regulated in all cells since imbalances in chromosomal copy number are deleterious and often lethal. In bacteria such as Bacillus subtilis and Escherichia coli, at the point of cytokinesis, there must be two complete copies of the chromosome to partition into the daughter cells following division at mid-cell during vegetative growth. Under conditions of rapid growth, when the time taken to replicate the chromosome exceeds the doubling time of the cells, there will be multiple initiations per cell cycle and daughter cells will inherit chromosomes that are already undergoing replication. In contrast, cells entering the sporulation pathway in B. subtilis can do so only during a short interval in the cell cycle when there are two, and only two, chromosomes per cell, one destined for the spore and one for the mother cell. Here, we briefly describe the overall process of DNA replication in bacteria before reviewing initiation of DNA replication in detail. The review covers DnaA-directed assembly of the replisome at oriC and the multitude of mechanisms of regulation of initiation, with a focus on the similarities and differences between E. coli and B. subtilis. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview Translesion Synthesis: Insights into the Selection and Switching of DNA Polymerases
Genes 2017, 8(1), 24; doi:10.3390/genes8010024
Received: 30 November 2016 / Revised: 4 January 2017 / Accepted: 4 January 2017 / Published: 10 January 2017
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Abstract
DNA replication is constantly challenged by DNA lesions, noncanonical DNA structures and difficult-to-replicate DNA sequences. Two major strategies to rescue a stalled replication fork and to ensure continuous DNA synthesis are: (1) template switching and recombination-dependent DNA synthesis; and (2) translesion synthesis (TLS)
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DNA replication is constantly challenged by DNA lesions, noncanonical DNA structures and difficult-to-replicate DNA sequences. Two major strategies to rescue a stalled replication fork and to ensure continuous DNA synthesis are: (1) template switching and recombination-dependent DNA synthesis; and (2) translesion synthesis (TLS) using specialized DNA polymerases to perform nucleotide incorporation opposite DNA lesions. The former pathway is mainly error-free, and the latter is error-prone and a major source of mutagenesis. An accepted model of translesion synthesis involves DNA polymerase switching steps between a replicative DNA polymerase and one or more TLS DNA polymerases. The mechanisms that govern the selection and exchange of specialized DNA polymerases for a given DNA lesion are not well understood. In this review, recent studies concerning the mechanisms of selection and switching of DNA polymerases in eukaryotic systems are summarized. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview PrimPol—Prime Time to Reprime
Genes 2017, 8(1), 20; doi:10.3390/genes8010020
Received: 4 November 2016 / Revised: 9 December 2016 / Accepted: 16 December 2016 / Published: 6 January 2017
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Abstract
The complex molecular machines responsible for genome replication encounter many obstacles during their progression along DNA. Tolerance of these obstructions is critical for efficient and timely genome duplication. In recent years, primase-polymerase (PrimPol) has emerged as a new player involved in maintaining eukaryotic
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The complex molecular machines responsible for genome replication encounter many obstacles during their progression along DNA. Tolerance of these obstructions is critical for efficient and timely genome duplication. In recent years, primase-polymerase (PrimPol) has emerged as a new player involved in maintaining eukaryotic replication fork progression. This versatile replicative enzyme, a member of the archaeo-eukaryotic primase (AEP) superfamily, has the capacity to perform a range of template-dependent and independent synthesis activities. Here, we discuss the emerging roles of PrimPol as a leading strand repriming enzyme and describe the mechanisms responsible for recruiting and regulating the enzyme during this process. This review provides an overview and update of the current PrimPol literature, as well as highlighting unanswered questions and potential future avenues of investigation. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview Maintenance of Genome Integrity: How Mammalian Cells Orchestrate Genome Duplication by Coordinating Replicative and Specialized DNA Polymerases
Genes 2017, 8(1), 19; doi:10.3390/genes8010019
Received: 11 November 2016 / Revised: 19 December 2016 / Accepted: 27 December 2016 / Published: 6 January 2017
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Abstract
Precise duplication of the human genome is challenging due to both its size and sequence complexity. DNA polymerase errors made during replication, repair or recombination are central to creating mutations that drive cancer and aging. Here, we address the regulation of human DNA
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Precise duplication of the human genome is challenging due to both its size and sequence complexity. DNA polymerase errors made during replication, repair or recombination are central to creating mutations that drive cancer and aging. Here, we address the regulation of human DNA polymerases, specifically how human cells orchestrate DNA polymerases in the face of stress to complete replication and maintain genome stability. DNA polymerases of the B-family are uniquely adept at accurate genome replication, but there are numerous situations in which one or more additional DNA polymerases are required to complete genome replication. Polymerases of the Y-family have been extensively studied in the bypass of DNA lesions; however, recent research has revealed that these polymerases play important roles in normal human physiology. Replication stress is widely cited as contributing to genome instability, and is caused by conditions leading to slowed or stalled DNA replication. Common Fragile Sites epitomize “difficult to replicate” genome regions that are particularly vulnerable to replication stress, and are associated with DNA breakage and structural variation. In this review, we summarize the roles of both the replicative and Y-family polymerases in human cells, and focus on how these activities are regulated during normal and perturbed genome replication. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview Mec1/ATR, the Program Manager of Nucleic Acids Inc.
Genes 2017, 8(1), 10; doi:10.3390/genes8010010
Received: 5 November 2016 / Revised: 19 December 2016 / Accepted: 22 December 2016 / Published: 28 December 2016
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Abstract
Eukaryotic cells are equipped with surveillance mechanisms called checkpoints to ensure proper execution of cell cycle events. Among these are the checkpoints that detect DNA damage or replication perturbations and coordinate cellular activities to maintain genome stability. At the forefront of damage sensing
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Eukaryotic cells are equipped with surveillance mechanisms called checkpoints to ensure proper execution of cell cycle events. Among these are the checkpoints that detect DNA damage or replication perturbations and coordinate cellular activities to maintain genome stability. At the forefront of damage sensing is an evolutionarily conserved molecule, known respectively in budding yeast and humans as Mec1 (Mitosis entry checkpoint 1) and ATR (Ataxia telangiectasia and Rad3-related protein). Through phosphorylation, Mec1/ATR activates downstream components of a signaling cascade to maintain nucleotide pool balance, protect replication fork integrity, regulate activation of origins of replication, coordinate DNA repair, and implement cell cycle delay. This list of functions continues to expand as studies have revealed that Mec1/ATR modularly interacts with various protein molecules in response to different cellular cues. Among these newly assigned functions is the regulation of RNA metabolism during checkpoint activation and the coordination of replication–transcription conflicts. In this review, I will highlight some of these new functions of Mec1/ATR with a focus on the yeast model organism. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview Mechanisms Governing DDK Regulation of the Initiation of DNA Replication
Genes 2017, 8(1), 3; doi:10.3390/genes8010003
Received: 1 November 2016 / Revised: 13 December 2016 / Accepted: 16 December 2016 / Published: 22 December 2016
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Abstract
The budding yeast Dbf4-dependent kinase (DDK) complex—comprised of cell division cycle (Cdc7) kinase and its regulatory subunit dumbbell former 4 (Dbf4)—is required to trigger the initiation of DNA replication through the phosphorylation of multiple minichromosome maintenance complex subunits 2-7 (Mcm2-7). DDK is also
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The budding yeast Dbf4-dependent kinase (DDK) complex—comprised of cell division cycle (Cdc7) kinase and its regulatory subunit dumbbell former 4 (Dbf4)—is required to trigger the initiation of DNA replication through the phosphorylation of multiple minichromosome maintenance complex subunits 2-7 (Mcm2-7). DDK is also a target of the radiation sensitive 53 (Rad53) checkpoint kinase in response to replication stress. Numerous investigations have determined mechanistic details, including the regions of Mcm2, Mcm4, and Mcm6 phosphorylated by DDK, and a number of DDK docking sites. Similarly, the way in which the Rad53 forkhead-associated 1 (FHA1) domain binds to DDK—involving both canonical and non-canonical interactions—has been elucidated. Recent work has revealed mutual promotion of DDK and synthetic lethal with dpb11-1 3 (Sld3) roles. While DDK phosphorylation of Mcm2-7 subunits facilitates their interaction with Sld3 at origins, Sld3 in turn stimulates DDK phosphorylation of Mcm2. Details of a mutually antagonistic relationship between DDK and Rap1-interacting factor 1 (Rif1) have also recently come to light. While Rif1 is able to reverse DDK-mediated Mcm2-7 complex phosphorylation by targeting the protein phosphatase glycogen 7 (Glc7) to origins, there is evidence to suggest that DDK can counteract this activity by binding to and phosphorylating Rif1. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview Regulation and Function of Cdt1; A Key Factor in Cell Proliferation and Genome Stability
Genes 2017, 8(1), 2; doi:10.3390/genes8010002
Received: 6 November 2016 / Revised: 13 December 2016 / Accepted: 14 December 2016 / Published: 22 December 2016
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Abstract
Successful cell proliferation requires efficient and precise genome duplication followed by accurate chromosome segregation. The Cdc10-dependent transcript 1 protein (Cdt1) is required for the first step in DNA replication, and in human cells Cdt1 is also required during mitosis. Tight cell cycle controls
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Successful cell proliferation requires efficient and precise genome duplication followed by accurate chromosome segregation. The Cdc10-dependent transcript 1 protein (Cdt1) is required for the first step in DNA replication, and in human cells Cdt1 is also required during mitosis. Tight cell cycle controls over Cdt1 abundance and activity are critical to normal development and genome stability. We review here recent advances in elucidating Cdt1 molecular functions in both origin licensing and kinetochore–microtubule attachment, and we describe the current understanding of human Cdt1 regulation. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview The Causes and Consequences of Topological Stress during DNA Replication
Genes 2016, 7(12), 134; doi:10.3390/genes7120134
Received: 31 October 2016 / Revised: 11 December 2016 / Accepted: 14 December 2016 / Published: 21 December 2016
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Abstract
The faithful replication of sister chromatids is essential for genomic integrity in every cell division. The replication machinery must overcome numerous difficulties in every round of replication, including DNA topological stress. Topological stress arises due to the double-stranded helical nature of DNA. When
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The faithful replication of sister chromatids is essential for genomic integrity in every cell division. The replication machinery must overcome numerous difficulties in every round of replication, including DNA topological stress. Topological stress arises due to the double-stranded helical nature of DNA. When the strands are pulled apart for replication to occur, the intertwining of the double helix must also be resolved or topological stress will arise. This intrinsic problem is exacerbated by specific chromosomal contexts encountered during DNA replication. The convergence of two replicons during termination, the presence of stable protein-DNA complexes and active transcription can all lead to topological stresses being imposed upon DNA replication. Here we describe how replication forks respond to topological stress by replication fork rotation and fork reversal. We also discuss the genomic contexts where topological stress is likely to occur in eukaryotes, focusing on the contribution of transcription. Finally, we describe how topological stress, and the ways forks respond to it, may contribute to genomic instability in cells. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview The Cell Killing Mechanisms of Hydroxyurea
Genes 2016, 7(11), 99; doi:10.3390/genes7110099
Received: 22 September 2016 / Revised: 3 November 2016 / Accepted: 9 November 2016 / Published: 17 November 2016
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Abstract
Hydroxyurea is a well-established inhibitor of ribonucleotide reductase that has a long history of scientific interest and clinical use for the treatment of neoplastic and non-neoplastic diseases. It is currently the staple drug for the management of sickle cell anemia and chronic myeloproliferative
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Hydroxyurea is a well-established inhibitor of ribonucleotide reductase that has a long history of scientific interest and clinical use for the treatment of neoplastic and non-neoplastic diseases. It is currently the staple drug for the management of sickle cell anemia and chronic myeloproliferative disorders. Due to its reversible inhibitory effect on DNA replication in various organisms, hydroxyurea is also commonly used in laboratories for cell cycle synchronization or generating replication stress. However, incubation with high concentrations or prolonged treatment with low doses of hydroxyurea can result in cell death and the DNA damage generated at arrested replication forks is generally believed to be the direct cause. Recent studies in multiple model organisms have shown that oxidative stress and several other mechanisms may contribute to the majority of the cytotoxic effect of hydroxyurea. This review aims to summarize the progress in our understanding of the cell-killing mechanisms of hydroxyurea, which may provide new insights towards the improvement of chemotherapies that employ this agent. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview Recovery from the DNA Replication Checkpoint
Genes 2016, 7(11), 94; doi:10.3390/genes7110094
Received: 26 September 2016 / Revised: 20 October 2016 / Accepted: 23 October 2016 / Published: 28 October 2016
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Abstract
Checkpoint recovery is integral to a successful checkpoint response. Checkpoint pathways monitor progress during cell division so that in the event of an error, the checkpoint is activated to block the cell cycle and activate repair pathways. Intrinsic to this process is that
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Checkpoint recovery is integral to a successful checkpoint response. Checkpoint pathways monitor progress during cell division so that in the event of an error, the checkpoint is activated to block the cell cycle and activate repair pathways. Intrinsic to this process is that once repair has been achieved, the checkpoint signaling pathway is inactivated and cell cycle progression resumes. We use the term “checkpoint recovery” to describe the pathways responsible for the inactivation of checkpoint signaling and cell cycle re-entry after the initial stress has been alleviated. The DNA replication or S-phase checkpoint monitors the integrity of DNA synthesis. When replication stress is encountered, replication forks are stalled, and the checkpoint signaling pathway is activated. Central to recovery from the S-phase checkpoint is the restart of stalled replication forks. If checkpoint recovery fails, stalled forks may become unstable and lead to DNA breaks or unusual DNA structures that are difficult to resolve, causing genomic instability. Alternatively, if cell cycle resumption mechanisms become uncoupled from checkpoint inactivation, cells with under-replicated DNA might proceed through the cell cycle, also diminishing genomic stability. In this review, we discuss the molecular mechanisms that contribute to inactivation of the S-phase checkpoint signaling pathway and the restart of replication forks during recovery from replication stress. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessErratum Erratum: Gu, S. et al. Error-Free Bypass of 7,8-dihydro-8-oxo-2′-deoxyguanosine by DNA Polymerase of Pseudomonas aeruginosa Phage PaP1. Genes 2017, 8, 18
Genes 2017, 8(3), 91; doi:10.3390/genes8030091
Received: 27 February 2017 / Revised: 27 February 2017 / Accepted: 27 February 2017 / Published: 3 March 2017
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(This article belongs to the Special Issue DNA Replication Controls)

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