Special Issue "Protective Mechanisms Against DNA Replication Stress"

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 January 2020).

Special Issue Editors

Prof. Anja Katrin Bielinsky
Website
Guest Editor
University of Minnesota Twin Cities, Minneapolis, United States
Interests: DNA replication; replication stress; DNA damage tolerance; genome instability
Dr. Bernard Lopez
Website
Guest Editor
Department of Development, Reproduction and Cancer, Institut Cochin, 75014 Paris, France
Interests: genome stability and instability; DNA double strand breaks; DNA integrity

Special Issue Information

Dear Colleagues,

Replication stress has emerged as one of the primary challenges our cells face when replicating their genome. Replication forks routinely encounter hindrances that stall the progression of DNA polymerases, such as abasic sites and some oxidized bases, higher-order structures that are difficult to replicate, and actively transcribed regions. Moreover, imbalanced nucleotide pools also affect replication dynamics. Replication fork stalling generates single-stranded DNA that triggers protective pathways that either enable the replication fork to restart or protect nascent DNA from degradation. Failure in these mechanisms leads to replisome disassembly and collapse into double-strand breaks. During mitosis, unresolved replication stress gives rise to anaphase bridges, fragile sites, and supernumerary centrosomes that lead to multipolar spindles and aneuploidy. Replication stress is therefore a major driving force of genome instability and has been proposed to be involved in early stages of cancer and senescence. Inhibitors of critical replication stress signaling cascades have gained clinical importance in recent years, as has our understanding of how replicative exhaustion accelerates aging and replicative DNA damage induces inflammation.

Prof. Anja Katrin Bielinsky
Dr. Bernard Lopez
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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 1800 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

  • ATR/CHK1 signaling
  • endogenous stress
  • environmental stressors
  • replication fork stalling
  • collapse and restart
  • endonucleolytic cleavage
  • mitotic catastrophe
  • replication stress-induced inflammation
  • transcription/replication conflict
  • nucleotide pool imbalance
  • cell cycle checkpoints
  • fragile sites
  • anaphase bridges
  • supernumerary centrosomes

Published Papers (7 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Review

Open AccessReview
Protective Mechanisms Against DNA Replication Stress in the Nervous System
Genes 2020, 11(7), 730; https://doi.org/10.3390/genes11070730 - 30 Jun 2020
Abstract
The precise replication of DNA and the successful segregation of chromosomes are essential for the faithful transmission of genetic information during the cell cycle. Alterations in the dynamics of genome replication, also referred to as DNA replication stress, may lead to DNA damage [...] Read more.
The precise replication of DNA and the successful segregation of chromosomes are essential for the faithful transmission of genetic information during the cell cycle. Alterations in the dynamics of genome replication, also referred to as DNA replication stress, may lead to DNA damage and, consequently, mutations and chromosomal rearrangements. Extensive research has revealed that DNA replication stress drives genome instability during tumorigenesis. Over decades, genetic studies of inherited syndromes have established a connection between the mutations in genes required for proper DNA repair/DNA damage responses and neurological diseases. It is becoming clear that both the prevention and the responses to replication stress are particularly important for nervous system development and function. The accurate regulation of cell proliferation is key for the expansion of progenitor pools during central nervous system (CNS) development, adult neurogenesis, and regeneration. Moreover, DNA replication stress in glial cells regulates CNS tumorigenesis and plays a role in neurodegenerative diseases such as ataxia telangiectasia (A-T). Here, we review how replication stress generation and replication stress response (RSR) contribute to the CNS development, homeostasis, and disease. Both cell-autonomous mechanisms, as well as the evidence of RSR-mediated alterations of the cellular microenvironment in the nervous system, were discussed. Full article
(This article belongs to the Special Issue Protective Mechanisms Against DNA Replication Stress)
Show Figures

Figure 1

Open AccessFeature PaperReview
DNA Replication Stress and Chromosomal Instability: Dangerous Liaisons
Genes 2020, 11(6), 642; https://doi.org/10.3390/genes11060642 - 10 Jun 2020
Abstract
Chromosomal instability (CIN) is associated with many human diseases, including neurodevelopmental or neurodegenerative conditions, age-related disorders and cancer, and is a key driver for disease initiation and progression. A major source of structural chromosome instability (s-CIN) leading to structural chromosome aberrations is “replication [...] Read more.
Chromosomal instability (CIN) is associated with many human diseases, including neurodevelopmental or neurodegenerative conditions, age-related disorders and cancer, and is a key driver for disease initiation and progression. A major source of structural chromosome instability (s-CIN) leading to structural chromosome aberrations is “replication stress”, a condition in which stalled or slowly progressing replication forks interfere with timely and error-free completion of the S phase. On the other hand, mitotic errors that result in chromosome mis-segregation are the cause of numerical chromosome instability (n-CIN) and aneuploidy. In this review, we will discuss recent evidence showing that these two forms of chromosomal instability can be mechanistically interlinked. We first summarize how replication stress causes structural and numerical CIN, focusing on mechanisms such as mitotic rescue of replication stress (MRRS) and centriole disengagement, which prevent or contribute to specific types of structural chromosome aberrations and segregation errors. We describe the main outcomes of segregation errors and how micronucleation and aneuploidy can be the key stimuli promoting inflammation, senescence, or chromothripsis. At the end, we discuss how CIN can reduce cellular fitness and may behave as an anticancer barrier in noncancerous cells or precancerous lesions, whereas it fuels genomic instability in the context of cancer, and how our current knowledge may be exploited for developing cancer therapies. Full article
(This article belongs to the Special Issue Protective Mechanisms Against DNA Replication Stress)
Show Figures

Figure 1

Open AccessReview
Location, Location, Location: The Role of Nuclear Positioning in the Repair of Collapsed Forks and Protection of Genome Stability
Genes 2020, 11(6), 635; https://doi.org/10.3390/genes11060635 - 09 Jun 2020
Abstract
Components of the nuclear pore complex (NPC) have been shown to play a crucial role in protecting against replication stress, and recovery from some types of stalled or collapsed replication forks requires movement of the DNA to the NPC in order to maintain [...] Read more.
Components of the nuclear pore complex (NPC) have been shown to play a crucial role in protecting against replication stress, and recovery from some types of stalled or collapsed replication forks requires movement of the DNA to the NPC in order to maintain genome stability. The role that nuclear positioning has on DNA repair has been investigated in several systems that inhibit normal replication. These include structure forming sequences (expanded CAG repeats), protein mediated stalls (replication fork barriers (RFBs)), stalls within the telomere sequence, and the use of drugs known to stall or collapse replication forks (HU + MMS or aphidicolin). Recently, the mechanism of relocation for collapsed replication forks to the NPC has been elucidated. Here, we will review the types of replication stress that relocate to the NPC, the current models for the mechanism of relocation, and the currently known protective effects of this movement. Full article
(This article belongs to the Special Issue Protective Mechanisms Against DNA Replication Stress)
Show Figures

Figure 1

Open AccessReview
CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication
Genes 2020, 11(6), 593; https://doi.org/10.3390/genes11060593 - 28 May 2020
Abstract
p21Waf/CIP1 is a small unstructured protein that binds and inactivates cyclin-dependent kinases (CDKs). To this end, p21 levels increase following the activation of the p53 tumor suppressor. CDK inhibition by p21 triggers cell-cycle arrest in the G1 and G2 phases of the [...] Read more.
p21Waf/CIP1 is a small unstructured protein that binds and inactivates cyclin-dependent kinases (CDKs). To this end, p21 levels increase following the activation of the p53 tumor suppressor. CDK inhibition by p21 triggers cell-cycle arrest in the G1 and G2 phases of the cell cycle. In the absence of exogenous insults causing replication stress, only residual p21 levels are prevalent that are insufficient to inhibit CDKs. However, research from different laboratories has demonstrated that these residual p21 levels in the S phase control DNA replication speed and origin firing to preserve genomic stability. Such an S-phase function of p21 depends fully on its ability to displace partners from chromatin-bound proliferating cell nuclear antigen (PCNA). Vice versa, PCNA also regulates p21 by preventing its upregulation in the S phase, even in the context of robust p21 induction by γ irradiation. Such a tight regulation of p21 in the S phase unveils the potential that CDK-independent functions of p21 may have for the improvement of cancer treatments. Full article
(This article belongs to the Special Issue Protective Mechanisms Against DNA Replication Stress)
Show Figures

Graphical abstract

Open AccessReview
The FANC/BRCA Pathway Releases Replication Blockades by Eliminating DNA Interstrand Cross-Links
Genes 2020, 11(5), 585; https://doi.org/10.3390/genes11050585 - 25 May 2020
Abstract
DNA interstrand cross-links (ICLs) represent a major barrier blocking DNA replication fork progression. ICL accumulation results in growth arrest and cell death—particularly in cell populations undergoing high replicative activity, such as cancer and leukemic cells. For this reason, agents able to induce DNA [...] Read more.
DNA interstrand cross-links (ICLs) represent a major barrier blocking DNA replication fork progression. ICL accumulation results in growth arrest and cell death—particularly in cell populations undergoing high replicative activity, such as cancer and leukemic cells. For this reason, agents able to induce DNA ICLs are widely used as chemotherapeutic drugs. However, ICLs are also generated in cells as byproducts of normal metabolic activities. Therefore, every cell must be capable of rescuing lCL-stalled replication forks while maintaining the genetic stability of the daughter cells in order to survive, replicate DNA and segregate chromosomes at mitosis. Inactivation of the Fanconi anemia/breast cancer-associated (FANC/BRCA) pathway by inherited mutations leads to Fanconi anemia (FA), a rare developmental, cancer-predisposing and chromosome-fragility syndrome. FANC/BRCA is the key hub for a complex and wide network of proteins that—upon rescuing ICL-stalled DNA replication forks—allows cell survival. Understanding how cells cope with ICLs is mandatory to ameliorate ICL-based anticancer therapies and provide the molecular basis to prevent or bypass cancer drug resistance. Here, we review our state-of-the-art understanding of the mechanisms involved in ICL resolution during DNA synthesis, with a major focus on how the FANC/BRCA pathway ensures DNA strand opening and prevents genomic instability. Full article
(This article belongs to the Special Issue Protective Mechanisms Against DNA Replication Stress)
Show Figures

Figure 1

Open AccessReview
Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response
Genes 2020, 11(4), 409; https://doi.org/10.3390/genes11040409 - 09 Apr 2020
Cited by 2
Abstract
Complete and accurate DNA replication is essential to genome stability maintenance during cellular division. However, cells are routinely challenged by endogenous as well as exogenous agents that threaten DNA stability. DNA breaks and the activation of the DNA damage response (DDR) arising from [...] Read more.
Complete and accurate DNA replication is essential to genome stability maintenance during cellular division. However, cells are routinely challenged by endogenous as well as exogenous agents that threaten DNA stability. DNA breaks and the activation of the DNA damage response (DDR) arising from endogenous replication stress have been observed at pre- or early stages of oncogenesis and senescence. Proper detection and signalling of DNA damage are essential for the autonomous cellular response in which the DDR regulates cell cycle progression and controls the repair machinery. In addition to this autonomous cellular response, replicative stress changes the cellular microenvironment, activating the innate immune response that enables the organism to protect itself against the proliferation of damaged cells. Thereby, the recent descriptions of the mechanisms of the pro-inflammatory response activation after replication stress, DNA damage and DDR defects constitute important conceptual novelties. Here, we review the links of replication, DNA damage and DDR defects to innate immunity activation by pro-inflammatory paracrine effects, highlighting the implications for human syndromes and immunotherapies. Full article
(This article belongs to the Special Issue Protective Mechanisms Against DNA Replication Stress)
Show Figures

Figure 1

Open AccessReview
Control of DNA Damage Bypass by Ubiquitylation of PCNA
Genes 2020, 11(2), 138; https://doi.org/10.3390/genes11020138 - 29 Jan 2020
Cited by 1
Abstract
DNA damage leads to genome instability by interfering with DNA replication. Cells possess several damage bypass pathways that mitigate the effects of DNA damage during replication. These pathways include translesion synthesis and template switching. These pathways are regulated largely through post-translational modifications of [...] Read more.
DNA damage leads to genome instability by interfering with DNA replication. Cells possess several damage bypass pathways that mitigate the effects of DNA damage during replication. These pathways include translesion synthesis and template switching. These pathways are regulated largely through post-translational modifications of proliferating cell nuclear antigen (PCNA), an essential replication accessory factor. Mono-ubiquitylation of PCNA promotes translesion synthesis, and K63-linked poly-ubiquitylation promotes template switching. This article will discuss the mechanisms of how these post-translational modifications of PCNA control these bypass pathways from a structural and biochemical perspective. We will focus on the structure and function of the E3 ubiquitin ligases Rad18 and Rad5 that facilitate the mono-ubiquitylation and poly-ubiquitylation of PCNA, respectively. We conclude by reviewing alternative ideas about how these post-translational modifications of PCNA regulate the assembly of the multi-protein complexes that promote damage bypass pathways. Full article
(This article belongs to the Special Issue Protective Mechanisms Against DNA Replication Stress)
Show Figures

Figure 1

Back to TopTop