scholarly journals Mechanisms for Maintaining Eukaryotic Replisome Progression in the Presence of DNA Damage

2021 ◽  
Vol 8 ◽  
Author(s):  
Thomas A. Guilliam
Keyword(s):  
Dna Damage ◽  
Single Molecule ◽  
Replication Fork ◽  
Genome Stability ◽  
Genome Duplication ◽  
Damage Tolerance ◽  
Tolerance Mechanisms ◽  
Dna Damage Tolerance ◽  
Replication Fork Progression ◽  
The Impact

The eukaryotic replisome coordinates template unwinding and nascent-strand synthesis to drive DNA replication fork progression and complete efficient genome duplication. During its advancement along the parental template, each replisome may encounter an array of obstacles including damaged and structured DNA that impede its progression and threaten genome stability. A number of mechanisms exist to permit replisomes to overcome such obstacles, maintain their progression, and prevent fork collapse. A combination of recent advances in structural, biochemical, and single-molecule approaches have illuminated the architecture of the replisome during unperturbed replication, rationalised the impact of impediments to fork progression, and enhanced our understanding of DNA damage tolerance mechanisms and their regulation. This review focusses on these studies to provide an updated overview of the mechanisms that support replisomes to maintain their progression on an imperfect template.

scholarly journals Maturation of telomere 3’-overhangs is linked to the replication stress response

2020 ◽  
Author(s):  
Erin E. Henninger ◽  
Pascale Jolivet ◽  
Emilie Fallet ◽  
Mohcen Benmounah ◽  
Zhou Xu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Stress Response ◽  
Ubiquitin Ligase ◽  
Replication Fork ◽  
Damage Tolerance ◽  
Dna Helicase ◽  
Dna Damage Tolerance ◽  
Telomeric Repeats ◽  
Telomere Replication

AbstractPassage of the replication fork through telomeric repeats necessitates additional DNA processing by DNA repair factors, to regenerate the terminal 3’-overhang structure at leading telomeres. These factors are prevented from promoting telomeric recombination or fusion by an uncharacterized mechanism. Here we show that Rad5, a DNA helicase and ubiquitin ligase involved in the DNA damage tolerance pathway, participates in this mechanism. Rad5 is enriched at telomeres during telomere replication. Accelerated senescence seen in the absence of telomerase and Rad5, can be compensated for by a pathway involving the Rad51 recombinase and counteracted by the helicase Srs2. However, this pathway is only active at short telomeres. Instead, the ubiquitous activity of Rad5 during telomere replication is necessary for the proper reconstitution of the telomeric 3’-overhang, indicating that Rad5 is required to coordinate telomere maturation during telomere replication.

scholarly journals Replication intermediate architecture reveals the chronology of DNA damage tolerance pathways at UV-stalled replication forks in human cells

2020 ◽  
Author(s):  
Yann Benureau ◽  
Caroline Pouvelle ◽  
Eliana Moreira Tavares ◽  
Pauline Dupaigne ◽  
Emmanuelle Despras ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Synthesis ◽  
Replication Fork ◽  
Damage Tolerance ◽  
Dna Lesions ◽  
Human Cells ◽  
Compensatory Mechanism ◽  
Dna Damage Tolerance ◽  
Replication Intermediate

AbstractDNA lesions in S phase threaten genome stability. The DNA damage tolerance (DDT) pathways overcome these obstacles and allow completion of DNA synthesis by the use of specialised translesion (TLS) DNA polymerases or through recombination-related processes. However, how these mechanisms coordinate with each other and with bulk replication remain elusive. To address these issues, we monitored the variation of replication intermediate architecture in response to ultraviolet irradiation using transmission electron microscopy. We show that the TLS polymerase η, able to accurately bypass the major UV lesion and mutated in the skin cancer-prone xeroderma pigmentosum variant (XPV) syndrome, acts at the replication fork to resolve uncoupling and prevent post-replicative gap accumulation. Repriming occurs as a compensatory mechanism when this on-the-fly mechanism cannot operate, and is therefore predominant in XPV cells. Interestingly, our data support a recombination-independent function of RAD51 at the replication fork to sustain repriming. Finally, we provide evidence for the post-replicative commitment of recombination in gap repair and for pioneering observations of in vivo recombination intermediates. Altogether, we propose a chronology of UV damage tolerance in human cells that highlights the key role of polη in shaping this response and ensuring the continuity of DNA synthesis.

DNA damage bypass pathways and their effect on mutagenesis in yeast

2020 ◽  
Author(s):  
Matan Arbel ◽  
Batia Liefshitz ◽  
Martin Kupiec
Keyword(s):  
Dna Damage ◽  
Damage Tolerance ◽  
Genetic Research ◽  
Tolerance Mechanisms ◽  
Dna Damage Tolerance ◽  
Yeast Saccharomyces Cerevisiae ◽  
Open Questions ◽  
Repair Mechanisms ◽  
Post Replication Repair ◽  
Error Prone Repair

ABSTRACT What is the origin of mutations? In contrast to the naïve notion that mutations are unfortunate accidents, genetic research in microorganisms has demonstrated that most mutations are created by genetically encoded error-prone repair mechanisms. However, error-free repair pathways also exist, and it is still unclear how cells decide when to use one repair method or the other. Here, we summarize what is known about the DNA damage tolerance mechanisms (also known as post-replication repair) for perhaps the best-studied organism, the yeast Saccharomyces cerevisiae. We describe the latest research, which has established the existence of at least two error-free and two error-prone inter-related mechanisms of damage tolerance that compete for the handling of spontaneous DNA damage. We explore what is known about the induction of mutations by DNA damage. We point to potential paradoxes and to open questions that still remain unanswered.

Abstract 3722: Extracellular arginine starvation imposes DNA replication fork stall and permits DNA damage tolerance

2020 ◽  
Author(s):  
Yi-Chang Wang ◽  
Andrew A. Kelso ◽  
Yi-Hsuan Chen ◽  
Chi-An Hsieh ◽  
Wei-Kai Chen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Replication Fork ◽  
Damage Tolerance ◽  
Dna Damage Tolerance

scholarly journals The Chromatin-binding Protein Spn1 contributes to Genome Instability in Saccharomyces cerevisiae

2018 ◽  
Author(s):  
Alison K. Thurston ◽  
Catherine A. Radebaugh ◽  
Adam R. Almeida ◽  
Juan Lucas Argueso ◽  
Laurie A. Stargell
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Cycle ◽  
Dna Damage ◽  
Genome Stability ◽  
Damage Tolerance ◽  
Genome Instability ◽  
Chromatin Binding ◽  
Dna Damage Tolerance ◽  
Template Switch

AbstractCells expend a large amount of energy to maintain their DNA sequence. DNA repair pathways, cell cycle checkpoint activation, proofreading polymerases, and chromatin structure are ways in which the cell minimizes changes to the genome. During replication, the DNA damage tolerance pathway allows the replication forks to bypass damage on the template strand. This avoids prolonged replication fork stalling, which can contribute to genome instability. The DNA damage tolerance pathway includes two sub-pathways: translesion synthesis and template switch. Post-translational modification of PCNA and the histone tails, cell cycle phase, and local DNA structure have all been shown to influence sub-pathway choice. Chromatin architecture contributes to maintaining genome stability by providing physical protection of the DNA and by regulating DNA processing pathways. As such, chromatin-binding factors have been implicated in maintaining genome stability. Using Saccharomyces cerevisiae, we examined the role of Spn1, a chromatin binding and transcription elongation factor, in DNA damage tolerance. Expression of a mutant allele of SPN1 results in increased resistance to the DNA damaging agent methyl methanesulfonate, lower spontaneous and damage-induced mutation rates, along with increased chronological lifespan. We attribute these effects to an increased usage of the template switch branch of the DNA damage tolerance pathway in the spn1 strain. This provides evidence for a role of wild type Spn1 in promoting genome instability, as well as having ties to overcoming replication stress and contributing to chronological aging.

scholarly journals Interferon-stimulated gene 15 accelerates replication fork progression inducing chromosomal breakage

2020 ◽  
Vol 219 (8) ◽  
Author(s):  
Maria Chiara Raso ◽  
Nikola Djoric ◽  
Franziska Walser ◽  
Sandra Hess ◽  
Fabian Marc Schmid ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Replication Fork ◽  
Genome Stability ◽  
Dna Helicase ◽  
Replication Forks ◽  
Chromosomal Breakage ◽  
Replication Fork Progression ◽  
Ubiquitin System ◽  
Interferon Stimulated Gene 15

DNA replication is highly regulated by the ubiquitin system, which plays key roles upon stress. The ubiquitin-like modifier ISG15 (interferon-stimulated gene 15) is induced by interferons, bacterial and viral infection, and DNA damage, but it is also constitutively expressed in many types of cancer, although its role in tumorigenesis is still largely elusive. Here, we show that ISG15 localizes at the replication forks, in complex with PCNA and the nascent DNA, where it regulates DNA synthesis. Indeed, high levels of ISG15, intrinsic or induced by interferon-β, accelerate DNA replication fork progression, resulting in extensive DNA damage and chromosomal aberrations. This effect is largely independent of ISG15 conjugation and relies on ISG15 functional interaction with the DNA helicase RECQ1, which promotes restart of stalled replication forks. Additionally, elevated ISG15 levels sensitize cells to cancer chemotherapeutic treatments. We propose that ISG15 up-regulation exposes cells to replication stress, impacting genome stability and response to genotoxic drugs.

scholarly journals Rad51 replication fork recruitment is required for DNA damage tolerance

2013 ◽  
Vol 32 (9) ◽  
pp. 1307-1321 ◽  
Author(s):  
Román González-Prieto ◽  
Ana M Muñoz-Cabello ◽  
María J Cabello-Lobato ◽  
Félix Prado
Keyword(s):  
Dna Damage ◽  
Replication Fork ◽  
Damage Tolerance ◽  
Dna Damage Tolerance
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