Special Issue "Chromosome Replication and Genome Integrity"

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

Deadline for manuscript submissions: closed (31 October 2018)

Special Issue Editor

Guest Editor
Dr. Dana Branzei

Fondazione IFOM Istituto Firc di Oncologia Molecolare, Milan, Italy
Website | E-Mail
Interests: Genome integrity; DNA replication; Chromosome structure; DNA repair

Special Issue Information

Dear Colleagues,

Genome replication is central for cellular proliferation and is critically implicated in several human diseases. Various factors associate with the replication fork, stably or transiently, to promote replication, globally or at specific genomic regions, such as telomeres and centromeres, and at genomic locations containing DNA lesions, structured DNA, repetitive segments, and heterochromatin. Some of the DNA metabolism reactions associated with genomic replication facilitate DNA synthesis and replication restart, activate or dampen DNA damage response pathways coordinating repair and/or the origin usage program, resolve topological intermediates arising from recombination or transcription-replication clashes, establish or disrupt chromatin modifications and chromosome structure. Deficiencies in these individual pathways associated with chromosome replication cause various human genetic disorders, or predispose to cancer and progeria. This Special Issue in Genes on “Chromosome Replication and Genome Integrity” will address the mechanisms through which processes responding to adverse genome perturbations occur, providing an overview of recent developments in specialized research topics and critical perspectives on upcoming challenges.

Sincerely,

Dr.  Dana Branzei
Guest Editor

Manuscript Submission Information

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Keywords

  • Chromosome replication
  • DNA damage tolerance and repair
  • Fragile genomic regions
  • Chromatin and chromosome structure
  • DNA damage response

Published Papers (28 papers)

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Research

Jump to: Review

Open AccessArticle Microhomology Selection for Microhomology Mediated End Joining in Saccharomyces cerevisiae
Received: 4 March 2019 / Revised: 26 March 2019 / Accepted: 28 March 2019 / Published: 8 April 2019
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Abstract
Microhomology-mediated end joining (MMEJ) anneals short, imperfect microhomologies flanking DNA breaks, producing repair products with deletions in a Ku- and RAD52-independent fashion. Puzzlingly, MMEJ preferentially selects certain microhomologies over others, even when multiple microhomologies are available. To define rules and parameters for [...] Read more.
Microhomology-mediated end joining (MMEJ) anneals short, imperfect microhomologies flanking DNA breaks, producing repair products with deletions in a Ku- and RAD52-independent fashion. Puzzlingly, MMEJ preferentially selects certain microhomologies over others, even when multiple microhomologies are available. To define rules and parameters for microhomology selection, we altered the length, the position, and the level of mismatches to the microhomologies flanking homothallic switching (HO) endonuclease-induced breaks and assessed their effect on MMEJ frequency and the types of repair product formation. We found that microhomology of eight to 20 base pairs carrying no more than 20% mismatches efficiently induced MMEJ. Deletion of MSH6 did not impact MMEJ frequency. MMEJ preferentially chose a microhomology pair that was more proximal from the break. Interestingly, MMEJ events preferentially retained the centromere proximal side of the HO break, while the sequences proximal to the telomere were frequently deleted. The asymmetry in the deletional profile among MMEJ products was reduced when HO was induced on the circular chromosome. The results provide insight into how cells search and select microhomologies for MMEJ in budding yeast. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessArticle Functional Comparison of XPF Missense Mutations Associated to Multiple DNA Repair Disorders
Received: 21 December 2018 / Revised: 11 January 2019 / Accepted: 11 January 2019 / Published: 17 January 2019
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Abstract
XPF endonuclease is one of the most important DNA repair proteins. Encoded by XPF/ERCC4, XPF provides the enzymatic activity of XPF-ERCC1 heterodimer, an endonuclease that incises at the 5’ side of various DNA lesions. XPF is essential for nucleotide excision [...] Read more.
XPF endonuclease is one of the most important DNA repair proteins. Encoded by XPF/ERCC4, XPF provides the enzymatic activity of XPF-ERCC1 heterodimer, an endonuclease that incises at the 5’ side of various DNA lesions. XPF is essential for nucleotide excision repair (NER) and interstrand crosslink repair (ICLR). XPF/ERCC4 mutations are associated with several human diseases: Xeroderma Pigmentosum (XP), Segmental Progeria (XFE), Fanconi Anemia (FA), Cockayne Syndrome (CS), and XP/CS combined disease (XPCSCD). Most affected individuals are compound heterozygotes for XPF/ERCC4 mutations complicating the identification of genotype/phenotype correlations. We report a detailed overview of NER and ICLR functional studies in human XPF-KO (knock-out) isogenic cells expressing six disease-specific pathogenic XPF amino acid substitution mutations. Ultraviolet (UV) sensitivity and unscheduled DNA synthesis (UDS) assays provide the most reliable information to discern mutations associated with ICLR impairment from mutations related to NER deficiency, whereas recovery of RNA synthesis (RRS) assays results hint to a possible role of XPF in resolving R-loops. Our functional studies demonstrate that a defined cellular phenotype cannot be easily correlated to each XPF mutation. Substituted positions along XPF sequences are not predictive of cellular phenotype nor reflect a particular disease. Therefore, in addition to mutation type, allelic interactions, protein stability and intracellular distribution of mutant proteins may also contribute to alter DNA repair pathways balance leading to clinically distinct disorders. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessArticle Stimulation of Replication Template-Switching by DNA-Protein Crosslinks
Received: 31 October 2018 / Revised: 10 December 2018 / Accepted: 12 December 2018 / Published: 27 December 2018
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Abstract
Covalent DNA protein crosslinks (DPCs) are common lesions that block replication. We examine here the consequence of DPCs on mutagenesis involving replicational template-switch reactions in Escherichia coli. 5-Azacytidine (5-azaC) is a potent mutagen for template-switching. This effect is dependent on DNA cytosine methylase [...] Read more.
Covalent DNA protein crosslinks (DPCs) are common lesions that block replication. We examine here the consequence of DPCs on mutagenesis involving replicational template-switch reactions in Escherichia coli. 5-Azacytidine (5-azaC) is a potent mutagen for template-switching. This effect is dependent on DNA cytosine methylase (Dcm), implicating the Dcm-DNA covalent complex trapped by 5-azaC as the initiator for mutagenesis. The leading strand of replication is more mutable than the lagging strand, which can be explained by blocks to the replicative helicase and/or fork regression. We find that template-switch mutagenesis induced by 5-azaC does not require double strand break repair via RecABCD; the ability to induce the SOS response is anti-mutagenic. Mutants in recB, but not recA, exhibit high constitutive rates of template-switching, and we suggest that RecBCD-mediated DNA degradation prevents template-switching associated with fork regression. A mutation in the DnaB fork helicase also promotes high levels of template-switching. We also find that other DPC-inducers, formaldehyde (a non-specific crosslinker) and ciprofloxacin (a topoisomerase II poison) are also strong mutagens for template-switching with similar genetic properties. Induction of mutations and genetic rearrangements that occur by template-switching may constitute a previously unrecognized component of the genotoxicity and genetic instability promoted by DPCs. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessArticle Fanconi Anaemia-Like Mph1 Helicase Backs up Rad54 and Rad5 to Circumvent Replication Stress-Driven Chromosome Bridges
Genes 2018, 9(11), 558; https://doi.org/10.3390/genes9110558
Received: 25 October 2018 / Revised: 13 November 2018 / Accepted: 13 November 2018 / Published: 17 November 2018
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Abstract
Homologous recombination (HR) is a preferred mechanism to deal with DNA replication impairments. However, HR synapsis gives rise to joint molecules (JMs) between the nascent sister chromatids, challenging chromosome segregation in anaphase. Joint molecules are resolved by the actions of several structure-selective endonucleases [...] Read more.
Homologous recombination (HR) is a preferred mechanism to deal with DNA replication impairments. However, HR synapsis gives rise to joint molecules (JMs) between the nascent sister chromatids, challenging chromosome segregation in anaphase. Joint molecules are resolved by the actions of several structure-selective endonucleases (SSEs), helicases and topoisomerases. Previously, we showed that yeast double mutants for the Mus81-Mms4 and Yen1 SSEs lead to anaphase bridges (ABs) after replication stress. Here, we have studied the role of the Mph1 helicase in preventing these anaphase aberrations. Mph1, the yeast ortholog of Fanconi anaemia protein M (FANCM), is involved in the removal of the D-loop, the first JM to arise in canonical HR. Surprisingly, the absence of Mph1 alone did not increase ABs; rather, it blocked cells in G2. Interestingly, in the search for genetic interactions with functionally related helicases and translocases, we found additive effects on the G2 block and post-G2 aberrations between mph1Δ and knockout mutants for Srs2, Rad54 and Rad5. Based on these interactions, we suggest that Mph1 acts coordinately with these helicases in the non-canonical HR-driven fork regression mechanism to bypass stalled replication forks. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessArticle Origins Left, Right, and Centre: Increasing the Number of Initiation Sites in the Escherichia coli Chromosome
Received: 27 June 2018 / Revised: 20 July 2018 / Accepted: 23 July 2018 / Published: 27 July 2018
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Abstract
The bacterium Escherichia coli contains a single circular chromosome with a defined architecture. DNA replication initiates at a single origin called oriC. Two replication forks are assembled and proceed in opposite directions until they fuse in a specialised zone opposite the origin. This [...] Read more.
The bacterium Escherichia coli contains a single circular chromosome with a defined architecture. DNA replication initiates at a single origin called oriC. Two replication forks are assembled and proceed in opposite directions until they fuse in a specialised zone opposite the origin. This termination area is flanked by polar replication fork pause sites that allow forks to enter, but not to leave. Thus, the chromosome is divided into two replichores, each replicated by a single replication fork. Recently, we analysed the replication parameters in E. coli cells, in which an ectopic origin termed oriZ was integrated in the right-hand replichore. Two major obstacles to replication were identified: (1) head-on replication–transcription conflicts at highly transcribed rrn operons, and (2) the replication fork trap. Here, we describe replication parameters in cells with ectopic origins, termed oriX and oriY, integrated into the left-hand replichore, and a triple origin construct with oriX integrated in the left-hand and oriZ in the right-hand replichore. Our data again highlight both replication–transcription conflicts and the replication fork trap as important obstacles to DNA replication, and we describe a number of spontaneous large genomic rearrangements which successfully alleviate some of the problems arising from having an additional origin in an ectopic location. However, our data reveal additional factors that impact efficient chromosome duplication, highlighting the complexity of chromosomal architecture. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Review

Jump to: Research

Open AccessReview Structure-Specific Endonucleases and the Resolution of Chromosome Underreplication
Received: 22 February 2019 / Revised: 11 March 2019 / Accepted: 13 March 2019 / Published: 19 March 2019
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Abstract
Complete genome duplication in every cell cycle is fundamental for genome stability and cell survival. However, chromosome replication is frequently challenged by obstacles that impede DNA replication fork (RF) progression, which subsequently causes replication stress (RS). Cells have evolved pathways of RF protection [...] Read more.
Complete genome duplication in every cell cycle is fundamental for genome stability and cell survival. However, chromosome replication is frequently challenged by obstacles that impede DNA replication fork (RF) progression, which subsequently causes replication stress (RS). Cells have evolved pathways of RF protection and restart that mitigate the consequences of RS and promote the completion of DNA synthesis prior to mitotic chromosome segregation. If there is entry into mitosis with underreplicated chromosomes, this results in sister-chromatid entanglements, chromosome breakage and rearrangements and aneuploidy in daughter cells. Here, we focus on the resolution of persistent replication intermediates by the structure-specific endonucleases (SSEs) MUS81, SLX1-SLX4 and GEN1. Their actions and a recently discovered pathway of mitotic DNA repair synthesis have emerged as important facilitators of replication completion and sister chromatid detachment in mitosis. As RS is induced by oncogene activation and is a common feature of cancer cells, any advances in our understanding of the molecular mechanisms related to chromosome underreplication have important biomedical implications. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview Holding All the Cards—How Fanconi Anemia Proteins Deal with Replication Stress and Preserve Genomic Stability
Received: 10 January 2019 / Revised: 14 February 2019 / Accepted: 15 February 2019 / Published: 22 February 2019
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Abstract
Fanconi anemia (FA) is a hereditary chromosomal instability disorder often displaying congenital abnormalities and characterized by a predisposition to progressive bone marrow failure (BMF) and cancer. Over the last 25 years since the discovery of the first linkage of genetic mutations to FA, [...] Read more.
Fanconi anemia (FA) is a hereditary chromosomal instability disorder often displaying congenital abnormalities and characterized by a predisposition to progressive bone marrow failure (BMF) and cancer. Over the last 25 years since the discovery of the first linkage of genetic mutations to FA, its molecular genetic landscape has expanded tremendously as it became apparent that FA is a disease characterized by a defect in a specific DNA repair pathway responsible for the correction of covalent cross-links between the two complementary strands of the DNA double helix. This pathway has become increasingly complex, with the discovery of now over 20 FA-linked genes implicated in interstrand cross-link (ICL) repair. Moreover, gene products known to be involved in double-strand break (DSB) repair, mismatch repair (MMR), and nucleotide excision repair (NER) play roles in the ICL response and repair of associated DNA damage. While ICL repair is predominantly coupled with DNA replication, it also can occur in non-replicating cells. DNA damage accumulation and hematopoietic stem cell failure are thought to contribute to the increased inflammation and oxidative stress prevalent in FA. Adding to its confounding nature, certain FA gene products are also engaged in the response to replication stress, caused endogenously or by agents other than ICL-inducing drugs. In this review, we discuss the mechanistic aspects of the FA pathway and the molecular defects leading to elevated replication stress believed to underlie the cellular phenotypes and clinical features of FA. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview DNA Replication Through Strand Displacement During Lagging Strand DNA Synthesis in Saccharomyces cerevisiae
Received: 11 January 2019 / Revised: 14 February 2019 / Accepted: 18 February 2019 / Published: 21 February 2019
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Abstract
This review discusses a set of experimental results that support the existence of extended strand displacement events during budding yeast lagging strand DNA synthesis. Starting from introducing the mechanisms and factors involved in leading and lagging strand DNA synthesis and some aspects of [...] Read more.
This review discusses a set of experimental results that support the existence of extended strand displacement events during budding yeast lagging strand DNA synthesis. Starting from introducing the mechanisms and factors involved in leading and lagging strand DNA synthesis and some aspects of the architecture of the eukaryotic replisome, we discuss studies on bacterial, bacteriophage and viral DNA polymerases with potent strand displacement activities. We describe proposed pathways of Okazaki fragment processing via short and long flaps, with a focus on experimental results obtained in Saccharomyces cerevisiae that suggest the existence of frequent and extended strand displacement events during eukaryotic lagging strand DNA synthesis, and comment on their implications for genome integrity. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview At the Beginning of the End and in the Middle of the Beginning: Structure and Maintenance of Telomeric DNA Repeats and Interstitial Telomeric Sequences
Received: 4 January 2019 / Revised: 30 January 2019 / Accepted: 30 January 2019 / Published: 5 February 2019
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Abstract
Tandem DNA repeats derived from the ancestral (TTAGGG)n run were first detected at chromosome ends of the majority of living organisms, hence the name telomeric DNA repeats. Subsequently, it has become clear that telomeric motifs are also present within chromosomes, and they were [...] Read more.
Tandem DNA repeats derived from the ancestral (TTAGGG)n run were first detected at chromosome ends of the majority of living organisms, hence the name telomeric DNA repeats. Subsequently, it has become clear that telomeric motifs are also present within chromosomes, and they were suitably called interstitial telomeric sequences (ITSs). It is well known that telomeric DNA repeats play a key role in chromosome stability, preventing end-to-end fusions and precluding the recurrent DNA loss during replication. Recent data suggest that ITSs are also important genomic elements as they confer its karyotype plasticity. In fact, ITSs appeared to be among the most unstable microsatellite sequences as they are highly length polymorphic and can trigger chromosomal fragility and gross chromosomal rearrangements. Importantly, mechanisms responsible for their instability appear to be similar to the mechanisms that maintain the length of genuine telomeres. This review compares the mechanisms of maintenance and dynamic properties of telomeric repeats and ITSs and discusses the implications of these dynamics on genome stability. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview Control of Eukaryotic DNA Replication Initiation—Mechanisms to Ensure Smooth Transitions
Received: 31 December 2018 / Revised: 25 January 2019 / Accepted: 25 January 2019 / Published: 29 January 2019
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Abstract
DNA replication differs from most other processes in biology in that any error will irreversibly change the nature of the cellular progeny. DNA replication initiation, therefore, is exquisitely controlled. Deregulation of this control can result in over-replication characterized by repeated initiation events at [...] Read more.
DNA replication differs from most other processes in biology in that any error will irreversibly change the nature of the cellular progeny. DNA replication initiation, therefore, is exquisitely controlled. Deregulation of this control can result in over-replication characterized by repeated initiation events at the same replication origin. Over-replication induces DNA damage and causes genomic instability. The principal mechanism counteracting over-replication in eukaryotes is a division of replication initiation into two steps—licensing and firing—which are temporally separated and occur at distinct cell cycle phases. Here, we review this temporal replication control with a specific focus on mechanisms ensuring the faultless transition between licensing and firing phases. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview Replication of G Quadruplex DNA
Received: 14 December 2018 / Revised: 21 January 2019 / Accepted: 23 January 2019 / Published: 29 January 2019
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Abstract
A cursory look at any textbook image of DNA replication might suggest that the complex machine that is the replisome runs smoothly along the chromosomal DNA. However, many DNA sequences can adopt non-B form secondary structures and these have the potential to impede [...] Read more.
A cursory look at any textbook image of DNA replication might suggest that the complex machine that is the replisome runs smoothly along the chromosomal DNA. However, many DNA sequences can adopt non-B form secondary structures and these have the potential to impede progression of the replisome. A picture is emerging in which the maintenance of processive DNA replication requires the action of a significant number of additional proteins beyond the core replisome to resolve secondary structures in the DNA template. By ensuring that DNA synthesis remains closely coupled to DNA unwinding by the replicative helicase, these factors prevent impediments to the replisome from causing genetic and epigenetic instability. This review considers the circumstances in which DNA forms secondary structures, the potential responses of the eukaryotic replisome to these impediments in the light of recent advances in our understanding of its structure and operation and the mechanisms cells deploy to remove secondary structure from the DNA. To illustrate the principles involved, we focus on one of the best understood DNA secondary structures, G quadruplexes (G4s), and on the helicases that promote their resolution. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview Mechanisms of DNA Damage Tolerance: Post-Translational Regulation of PCNA
Received: 16 November 2018 / Revised: 18 December 2018 / Accepted: 19 December 2018 / Published: 24 December 2018
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Abstract
DNA damage is a constant source of stress challenging genomic integrity. To ensure faithful duplication of our genomes, mechanisms have evolved to deal with damage encountered during replication. One such mechanism is referred to as DNA damage tolerance (DDT). DDT allows for replication [...] Read more.
DNA damage is a constant source of stress challenging genomic integrity. To ensure faithful duplication of our genomes, mechanisms have evolved to deal with damage encountered during replication. One such mechanism is referred to as DNA damage tolerance (DDT). DDT allows for replication to continue in the presence of a DNA lesion by promoting damage bypass. Two major DDT pathways exist: error-prone translesion synthesis (TLS) and error-free template switching (TS). TLS recruits low-fidelity DNA polymerases to directly replicate across the damaged template, whereas TS uses the nascent sister chromatid as a template for bypass. Both pathways must be tightly controlled to prevent the accumulation of mutations that can occur from the dysregulation of DDT proteins. A key regulator of error-prone versus error-free DDT is the replication clamp, proliferating cell nuclear antigen (PCNA). Post-translational modifications (PTMs) of PCNA, mainly by ubiquitin and SUMO (small ubiquitin-like modifier), play a critical role in DDT. In this review, we will discuss the different types of PTMs of PCNA and how they regulate DDT in response to replication stress. We will also cover the roles of PCNA PTMs in lagging strand synthesis, meiotic recombination, as well as somatic hypermutation and class switch recombination. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview SMC5/6: Multifunctional Player in Replication
Received: 3 December 2018 / Revised: 18 December 2018 / Accepted: 19 December 2018 / Published: 22 December 2018
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Abstract
The genome replication process is challenged at many levels. Replication must proceed through different problematic sites and obstacles, some of which can pause or even reverse the replication fork (RF). In addition, replication of DNA within chromosomes must deal with their topological constraints [...] Read more.
The genome replication process is challenged at many levels. Replication must proceed through different problematic sites and obstacles, some of which can pause or even reverse the replication fork (RF). In addition, replication of DNA within chromosomes must deal with their topological constraints and spatial organization. One of the most important factors organizing DNA into higher-order structures are Structural Maintenance of Chromosome (SMC) complexes. In prokaryotes, SMC complexes ensure proper chromosomal partitioning during replication. In eukaryotes, cohesin and SMC5/6 complexes assist in replication. Interestingly, the SMC5/6 complexes seem to be involved in replication in many ways. They stabilize stalled RFs, restrain RF regression, participate in the restart of collapsed RFs, and buffer topological constraints during RF progression. In this (mini) review, I present an overview of these replication-related functions of SMC5/6. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview Regulation of Structure-Specific Endonucleases in Replication Stress
Genes 2018, 9(12), 634; https://doi.org/10.3390/genes9120634
Received: 9 November 2018 / Revised: 11 December 2018 / Accepted: 12 December 2018 / Published: 14 December 2018
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Abstract
Replication stress results in various forms of aberrant replication intermediates that need to be resolved for faithful chromosome segregation. Structure-specific endonucleases (SSEs) recognize DNA secondary structures rather than primary sequences and play key roles during DNA repair and replication stress. Holliday junction resolvase [...] Read more.
Replication stress results in various forms of aberrant replication intermediates that need to be resolved for faithful chromosome segregation. Structure-specific endonucleases (SSEs) recognize DNA secondary structures rather than primary sequences and play key roles during DNA repair and replication stress. Holliday junction resolvase MUS81 (methyl methane sulfonate (MMS), and UV-sensitive protein 81) and XPF (xeroderma pigmentosum group F-complementing protein) are a subset of SSEs that resolve aberrant replication structures. To ensure genome stability and prevent unnecessary DNA breakage, these SSEs are tightly regulated by the cell cycle and replication checkpoints. We discuss the regulatory network that control activities of MUS81 and XPF and briefly mention other SSEs involved in the resolution of replication intermediates. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview Endogenous DNA Double-Strand Breaks during DNA Transactions: Emerging Insights and Methods for Genome-Wide Profiling
Genes 2018, 9(12), 632; https://doi.org/10.3390/genes9120632
Received: 9 November 2018 / Revised: 11 December 2018 / Accepted: 12 December 2018 / Published: 14 December 2018
Cited by 2 | PDF Full-text (1316 KB) | HTML Full-text | XML Full-text
Abstract
DNA double-strand breaks (DSBs) jeopardize genome integrity and can—when repaired unfaithfully—give rise to structural rearrangements associated with cancer. Exogenous agents such as ionizing radiation or chemotherapy can invoke DSBs, but a vast amount of breakage arises during vital endogenous DNA transactions, such as [...] Read more.
DNA double-strand breaks (DSBs) jeopardize genome integrity and can—when repaired unfaithfully—give rise to structural rearrangements associated with cancer. Exogenous agents such as ionizing radiation or chemotherapy can invoke DSBs, but a vast amount of breakage arises during vital endogenous DNA transactions, such as replication and transcription. Additionally, chromatin looping involved in 3D genome organization and gene regulation is increasingly recognized as a possible contributor to DSB events. In this review, we first discuss insights into the mechanisms of endogenous DSB formation, showcasing the trade-off between essential DNA transactions and the intrinsic challenges that these processes impose on genomic integrity. In the second part, we highlight emerging methods for genome-wide profiling of DSBs, and discuss future directions of research that will help advance our understanding of genome-wide DSB formation and repair. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview RAD-ical New Insights into RAD51 Regulation
Genes 2018, 9(12), 629; https://doi.org/10.3390/genes9120629
Received: 19 November 2018 / Revised: 4 December 2018 / Accepted: 7 December 2018 / Published: 13 December 2018
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Abstract
The accurate repair of DNA is critical for genome stability and cancer prevention. DNA double-strand breaks are one of the most toxic lesions; however, they can be repaired using homologous recombination. Homologous recombination is a high-fidelity DNA repair pathway that uses a homologous [...] Read more.
The accurate repair of DNA is critical for genome stability and cancer prevention. DNA double-strand breaks are one of the most toxic lesions; however, they can be repaired using homologous recombination. Homologous recombination is a high-fidelity DNA repair pathway that uses a homologous template for repair. One central HR step is RAD51 nucleoprotein filament formation on the single-stranded DNA ends, which is a step required for the homology search and strand invasion steps of HR. RAD51 filament formation is tightly controlled by many positive and negative regulators, which are collectively termed the RAD51 mediators. The RAD51 mediators function to nucleate, elongate, stabilize, and disassemble RAD51 during repair. In model organisms, RAD51 paralogs are RAD51 mediator proteins that structurally resemble RAD51 and promote its HR activity. New functions for the RAD51 paralogs during replication and in RAD51 filament flexibility have recently been uncovered. Mutations in the human RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3, and SWSAP1) are found in a subset of breast and ovarian cancers. Despite their discovery three decades ago, few advances have been made in understanding the function of the human RAD51 paralogs. Here, we discuss the current perspective on the in vivo and in vitro function of the RAD51 paralogs, and their relationship with cancer in vertebrate models. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview The Unresolved Problem of DNA Bridging
Genes 2018, 9(12), 623; https://doi.org/10.3390/genes9120623
Received: 12 November 2018 / Revised: 8 December 2018 / Accepted: 10 December 2018 / Published: 12 December 2018
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Abstract
Accurate duplication and transmission of identical genetic information into offspring cells lies at the heart of a cell division cycle. During the last stage of cellular division, namely mitosis, the fully replicated DNA molecules are condensed into X-shaped chromosomes, followed by a chromosome [...] Read more.
Accurate duplication and transmission of identical genetic information into offspring cells lies at the heart of a cell division cycle. During the last stage of cellular division, namely mitosis, the fully replicated DNA molecules are condensed into X-shaped chromosomes, followed by a chromosome separation process called sister chromatid disjunction. This process allows for the equal partition of genetic material into two newly born daughter cells. However, emerging evidence has shown that faithful chromosome segregation is challenged by the presence of persistent DNA intertwining structures generated during DNA replication and repair, which manifest as so-called ultra-fine DNA bridges (UFBs) during anaphase. Undoubtedly, failure to disentangle DNA linkages poses a severe threat to mitosis and genome integrity. This review will summarize the possible causes of DNA bridges, particularly sister DNA inter-linkage structures, in an attempt to explain how they may be processed and how they influence faithful chromosome segregation and the maintenance of genome stability. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview Chromatin as a Platform for Modulating the Replication Stress Response
Genes 2018, 9(12), 622; https://doi.org/10.3390/genes9120622
Received: 30 October 2018 / Revised: 3 December 2018 / Accepted: 4 December 2018 / Published: 11 December 2018
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Abstract
Eukaryotic DNA replication occurs in the context of chromatin. Recent years have seen major advances in our understanding of histone supply, histone recycling and nascent histone incorporation during replication. Furthermore, much is now known about the roles of histone remodellers and post-translational modifications [...] Read more.
Eukaryotic DNA replication occurs in the context of chromatin. Recent years have seen major advances in our understanding of histone supply, histone recycling and nascent histone incorporation during replication. Furthermore, much is now known about the roles of histone remodellers and post-translational modifications in replication. It has also become clear that nucleosome dynamics during replication play critical roles in genome maintenance and that chromatin modifiers are important for preventing DNA replication stress. An understanding of how cells deploy specific nucleosome modifiers, chaperones and remodellers directly at sites of replication fork stalling has been building more slowly. Here we will specifically discuss recent advances in understanding how chromatin composition contribute to replication fork stability and restart. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview Repetitive Fragile Sites: Centromere Satellite DNA as a Source of Genome Instability in Human Diseases
Genes 2018, 9(12), 615; https://doi.org/10.3390/genes9120615
Received: 5 November 2018 / Revised: 3 December 2018 / Accepted: 3 December 2018 / Published: 7 December 2018
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Abstract
Maintenance of an intact genome is essential for cellular and organismal homeostasis. The centromere is a specialized chromosomal locus required for faithful genome inheritance at each round of cell division. Human centromeres are composed of large tandem arrays of repetitive alpha-satellite DNA, which [...] Read more.
Maintenance of an intact genome is essential for cellular and organismal homeostasis. The centromere is a specialized chromosomal locus required for faithful genome inheritance at each round of cell division. Human centromeres are composed of large tandem arrays of repetitive alpha-satellite DNA, which are often sites of aberrant rearrangements that may lead to chromosome fusions and genetic abnormalities. While the centromere has an essential role in chromosome segregation during mitosis, the long and repetitive nature of the highly identical repeats has greatly hindered in-depth genetic studies, and complete annotation of all human centromeres is still lacking. Here, we review our current understanding of human centromere genetics and epigenetics as well as recent investigations into the role of centromere DNA in disease, with a special focus on cancer, aging, and human immunodeficiency–centromeric instability–facial anomalies (ICF) syndrome. We also highlight the causes and consequences of genomic instability at these large repetitive arrays and describe the possible sources of centromere fragility. The novel connection between alpha-satellite DNA instability and human pathological conditions emphasizes the importance of obtaining a truly complete human genome assembly and accelerating our understanding of centromere repeats’ role in physiology and beyond. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview DNA Damage Tolerance Mechanisms Revealed from the Analysis of Immunoglobulin V Gene Diversification in Avian DT40 Cells
Genes 2018, 9(12), 614; https://doi.org/10.3390/genes9120614
Received: 30 October 2018 / Revised: 26 November 2018 / Accepted: 30 November 2018 / Published: 7 December 2018
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Abstract
DNA replication is an essential biochemical reaction in dividing cells that frequently stalls at damaged sites. Homologous/homeologous recombination (HR)-mediated template switch and translesion DNA synthesis (TLS)-mediated bypass processes release arrested DNA replication forks. These mechanisms are pivotal for replication fork maintenance and play [...] Read more.
DNA replication is an essential biochemical reaction in dividing cells that frequently stalls at damaged sites. Homologous/homeologous recombination (HR)-mediated template switch and translesion DNA synthesis (TLS)-mediated bypass processes release arrested DNA replication forks. These mechanisms are pivotal for replication fork maintenance and play critical roles in DNA damage tolerance (DDT) and gap-filling. The avian DT40 B lymphocyte cell line provides an opportunity to examine HR-mediated template switch and TLS triggered by abasic sites by sequencing the constitutively diversifying immunoglobulin light-chain variable gene (IgV). During IgV diversification, activation-induced deaminase (AID) converts dC to dU, which in turn is excised by uracil DNA glycosylase and yields abasic sites within a defined window of around 500 base pairs. These abasic sites can induce gene conversion with a set of homeologous upstream pseudogenes via the HR-mediated template switch, resulting in templated mutagenesis, or can be bypassed directly by TLS, resulting in non-templated somatic hypermutation at dC/dG base pairs. In this review, we discuss recent works unveiling IgV diversification mechanisms in avian DT40 cells, which shed light on DDT mode usage in vertebrate cells and tolerance of abasic sites. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview Homologous Recombination: To Fork and Beyond
Genes 2018, 9(12), 603; https://doi.org/10.3390/genes9120603
Received: 9 November 2018 / Revised: 29 November 2018 / Accepted: 29 November 2018 / Published: 4 December 2018
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Abstract
Accurate completion of genome duplication is threatened by multiple factors that hamper the advance and stability of the replication forks. Cells need to tolerate many of these blocking lesions to timely complete DNA replication, postponing their repair for later. This process of lesion [...] Read more.
Accurate completion of genome duplication is threatened by multiple factors that hamper the advance and stability of the replication forks. Cells need to tolerate many of these blocking lesions to timely complete DNA replication, postponing their repair for later. This process of lesion bypass during DNA damage tolerance can lead to the accumulation of single-strand DNA (ssDNA) fragments behind the fork, which have to be filled in before chromosome segregation. Homologous recombination plays essential roles both at and behind the fork, through fork protection/lesion bypass and post-replicative ssDNA filling processes, respectively. I review here our current knowledge about the recombination mechanisms that operate at and behind the fork in eukaryotes, and how these mechanisms are controlled to prevent unscheduled and toxic recombination intermediates. A unifying model to integrate these mechanisms in a dynamic, replication fork-associated process is proposed from yeast results. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview Role of the Mre11 Complex in Preserving Genome Integrity
Genes 2018, 9(12), 589; https://doi.org/10.3390/genes9120589
Received: 12 November 2018 / Revised: 26 November 2018 / Accepted: 27 November 2018 / Published: 29 November 2018
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Abstract
DNA double-strand breaks (DSBs) are hazardous lesions that threaten genome integrity and cell survival. The DNA damage response (DDR) safeguards the genome by sensing DSBs, halting cell cycle progression and promoting repair through either non-homologous end joining (NHEJ) or homologous recombination (HR). The [...] Read more.
DNA double-strand breaks (DSBs) are hazardous lesions that threaten genome integrity and cell survival. The DNA damage response (DDR) safeguards the genome by sensing DSBs, halting cell cycle progression and promoting repair through either non-homologous end joining (NHEJ) or homologous recombination (HR). The Mre11-Rad50-Xrs2/Nbs1 (MRX/N) complex is central to the DDR through its structural, enzymatic, and signaling roles. The complex tethers DNA ends, activates the Tel1/ATM kinase, resolves protein-bound or hairpin-capped DNA ends, and maintains telomere homeostasis. In addition to its role at DSBs, MRX/N associates with unperturbed replication forks, as well as stalled replication forks, to ensure complete DNA synthesis and to prevent chromosome rearrangements. Here, we summarize the significant progress made in characterizing the MRX/N complex and its various activities in chromosome metabolism. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview The Emerging Role of Cohesin in the DNA Damage Response
Genes 2018, 9(12), 581; https://doi.org/10.3390/genes9120581
Received: 29 October 2018 / Revised: 20 November 2018 / Accepted: 21 November 2018 / Published: 28 November 2018
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Abstract
Faithful transmission of genetic material is crucial for all organisms since changes in genetic information may result in genomic instability that causes developmental disorders and cancers. Thus, understanding the mechanisms that preserve genome integrity is of fundamental importance. Cohesin is a multiprotein complex [...] Read more.
Faithful transmission of genetic material is crucial for all organisms since changes in genetic information may result in genomic instability that causes developmental disorders and cancers. Thus, understanding the mechanisms that preserve genome integrity is of fundamental importance. Cohesin is a multiprotein complex whose canonical function is to hold sister chromatids together from S-phase until the onset of anaphase to ensure the equal division of chromosomes. However, recent research points to a crucial function of cohesin in the DNA damage response (DDR). In this review, we summarize recent advances in the understanding of cohesin function in DNA damage signaling and repair. First, we focus on cohesin architecture and molecular mechanisms that govern sister chromatid cohesion. Next, we briefly characterize the main DDR pathways. Finally, we describe mechanisms that determine cohesin accumulation at DNA damage sites and discuss possible roles of cohesin in DDR. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview Common Chromosomal Fragile Sites—Conserved Failure Stories
Genes 2018, 9(12), 580; https://doi.org/10.3390/genes9120580
Received: 31 October 2018 / Revised: 19 November 2018 / Accepted: 21 November 2018 / Published: 27 November 2018
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Abstract
In order to pass on an intact copy of the genome during cell division, complete and faithful DNA replication is crucial. Yet, certain areas of the genome are intrinsically challenging to replicate, which manifests as high local mutation propensity. Such regions include trinucleotide [...] Read more.
In order to pass on an intact copy of the genome during cell division, complete and faithful DNA replication is crucial. Yet, certain areas of the genome are intrinsically challenging to replicate, which manifests as high local mutation propensity. Such regions include trinucleotide repeat sequences, common chromosomal fragile sites (CFSs), and early replicating fragile sites (ERFSs). Despite their genomic instability CFSs are conserved, suggesting that they have a biological function. To shed light on the potential function of CFSs, this review summarizes the similarities and differences of the regions that challenge DNA replication with main focus on CFSs. Moreover, we review the mechanisms that operate when CFSs fail to complete replication before entry into mitosis. Finally, evolutionary perspectives and potential physiological roles of CFSs are discussed with emphasis on their potential role in neurogenesis. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview Coping with Reactive Oxygen Species to Ensure Genome Stability in Escherichia coli
Genes 2018, 9(11), 565; https://doi.org/10.3390/genes9110565
Received: 26 October 2018 / Revised: 15 November 2018 / Accepted: 16 November 2018 / Published: 21 November 2018
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Abstract
The facultative aerobic bacterium Escherichia coli adjusts its cell cycle to environmental conditions. Because of its lifestyle, the bacterium has to balance the use of oxygen with the potential lethal effects of its poisonous derivatives. Oxidative damages perpetrated by molecules such as hydrogen [...] Read more.
The facultative aerobic bacterium Escherichia coli adjusts its cell cycle to environmental conditions. Because of its lifestyle, the bacterium has to balance the use of oxygen with the potential lethal effects of its poisonous derivatives. Oxidative damages perpetrated by molecules such as hydrogen peroxide and superoxide anions directly incapacitate metabolic activities relying on enzymes co-factored with iron and flavins. Consequently, growth is inhibited when the bacterium faces substantial reactive oxygen insults coming from environmental or cellular sources. Although hydrogen peroxide and superoxide anions do not oxidize DNA directly, these molecules feed directly or indirectly the generation of the highly reactive hydroxyl radical that damages the bacterial chromosome. Oxidized bases are normally excised and the single strand gap repaired by the base excision repair pathway (BER). This process is especially problematic in E. coli because replication forks do not sense the presence of damages or a stalled fork ahead of them. As consequence, single-strand breaks are turned into double-strand breaks (DSB) through replication. Since E. coli tolerates the presence of DSBs poorly, BER can become toxic during oxidative stress. Here we review the repair strategies that E. coli adopts to preserve genome integrity during oxidative stress and their relation to cell cycle control of DNA replication. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview Molecular and Cellular Functions of the Warsaw Breakage Syndrome DNA Helicase DDX11
Genes 2018, 9(11), 564; https://doi.org/10.3390/genes9110564
Received: 31 October 2018 / Revised: 17 November 2018 / Accepted: 19 November 2018 / Published: 21 November 2018
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Abstract
DDX11/ChlR1 (Chl1 in yeast) is a DNA helicase involved in sister chromatid cohesion and in DNA repair pathways. The protein belongs to the family of the iron–sulphur cluster containing DNA helicases, whose deficiencies have been linked to a number of diseases affecting genome [...] Read more.
DDX11/ChlR1 (Chl1 in yeast) is a DNA helicase involved in sister chromatid cohesion and in DNA repair pathways. The protein belongs to the family of the iron–sulphur cluster containing DNA helicases, whose deficiencies have been linked to a number of diseases affecting genome stability. Mutations of human DDX11 are indeed associated with the rare genetic disorder named Warsaw breakage syndrome, showing both chromosomal breakages and chromatid cohesion defects. Moreover, growing evidence of a potential role in oncogenesis further emphasizes the clinical relevance of DDX11. Here, we illustrate the biochemical and structural features of DDX11 and how it cooperates with multiple protein partners in the cell, acting at the interface of DNA replication/repair/recombination and sister chromatid cohesion to preserve genome stability. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview Genome Instability Induced by Low Levels of Replicative DNA Polymerases in Yeast
Genes 2018, 9(11), 539; https://doi.org/10.3390/genes9110539
Received: 24 October 2018 / Revised: 4 November 2018 / Accepted: 5 November 2018 / Published: 7 November 2018
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Abstract
Most cells of solid tumors have very high levels of genome instability of several different types, including deletions, duplications, translocations, and aneuploidy. Much of this instability appears induced by DNA replication stress. As a model for understanding this type of instability, we have [...] Read more.
Most cells of solid tumors have very high levels of genome instability of several different types, including deletions, duplications, translocations, and aneuploidy. Much of this instability appears induced by DNA replication stress. As a model for understanding this type of instability, we have examined genome instability in yeast strains that have low levels of two of the replicative DNA polymerases: DNA polymerase α and DNA polymerase δ (Polα and Polδ). We show that low levels of either of these DNA polymerases results in greatly elevated levels of mitotic recombination, chromosome rearrangements, and deletions/duplications. The spectrum of events in the two types of strains, however, differs in a variety of ways. For example, a reduced level of Polδ elevates single-base alterations and small deletions considerably more than a reduced level of Polα. In this review, we will summarize the methods used to monitor genome instability in yeast, and how this analysis contributes to understanding the linkage between genome instability and DNA replication stress. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessFeature PaperReview Maneuvers on PCNA Rings during DNA Replication and Repair
Received: 19 July 2018 / Revised: 8 August 2018 / Accepted: 9 August 2018 / Published: 17 August 2018
Cited by 2 | PDF Full-text (9171 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
DNA replication and repair are essential cellular processes that ensure genome duplication and safeguard the genome from deleterious mutations. Both processes utilize an abundance of enzymatic functions that need to be tightly regulated to ensure dynamic exchange of DNA replication and repair factors. [...] Read more.
DNA replication and repair are essential cellular processes that ensure genome duplication and safeguard the genome from deleterious mutations. Both processes utilize an abundance of enzymatic functions that need to be tightly regulated to ensure dynamic exchange of DNA replication and repair factors. Proliferating cell nuclear antigen (PCNA) is the major coordinator of faithful and processive replication and DNA repair at replication forks. Post-translational modifications of PCNA, ubiquitination and acetylation in particular, regulate the dynamics of PCNA-protein interactions. Proliferating cell nuclear antigen (PCNA) monoubiquitination elicits ‘polymerase switching’, whereby stalled replicative polymerase is replaced with a specialized polymerase, while PCNA acetylation may reduce the processivity of replicative polymerases to promote homologous recombination-dependent repair. While regulatory functions of PCNA ubiquitination and acetylation have been well established, the regulation of PCNA-binding proteins remains underexplored. Considering the vast number of PCNA-binding proteins, many of which have similar PCNA binding affinities, the question arises as to the regulation of the strength and sequence of their binding to PCNA. Here I provide an overview of post-translational modifications on both PCNA and PCNA-interacting proteins and discuss their relevance for the regulation of the dynamic processes of DNA replication and repair. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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