Securing genome stability by orchestrating DNA repair: removal of radiation-induced clustered lesions in DNA

BioEssays ◽  
2001 ◽  
Vol 23 (8) ◽  
pp. 745-749 ◽  
Author(s):  
Grigory L. Dianov ◽  
Peter O'Neill ◽  
Dudley T. Goodhead
Keyword(s):  
Dna Repair ◽  
Genome Stability ◽  
Radiation Induced

scholarly journals Involvement of DNA Repair Genes and System of Radiation-Induced Activation of Transposons in Formation of Transgenerational Effects

2020 ◽  
Vol 11 ◽  
Author(s):  
Elena Yushkova
Keyword(s):  
Dna Repair ◽  
Genome Stability ◽  
Specific Response ◽  
Dna Breaks ◽  
Transgenerational Effects ◽  
Transpositional Activity ◽  
Effective Strategies ◽  
Radiation Induced ◽  
Mechanisms Of Adaptation ◽  
Transposon Activity

The study of the genetic basis of the manifestation of radiation-induced effects and their transgenerational inheritance makes it possible to identify the mechanisms of adaptation and possible effective strategies for the survival of organisms in response to chronic radioactive stress. One persistent hypothesis is that the activation of certain genes involved in cellular defense is a specific response of the cell to irradiation. There is also data indicating the important role of transposable elements in the formation of radiosensitivity/radioresistance of biological systems. In this work, we studied the interaction of the systems of hobo transposon activity and DNA repair in the cell under conditions of chronic low-dose irradiation and its participation in the inheritance of radiation-induced transgenerational instability in Drosophila. Our results showed a significant increase of sterility and locus-specific mutability, a decrease of survival, fertility and genome stability (an increase the frequency of dominant lethal mutations and DNA damage) in non-irradiated F1/F2 offspring of irradiated parents with dysfunction of the mus304 gene which is responsible for excision and post-replicative recombination repair and repair of double-stranded DNA breaks. The combined action of dysfunction of the mus309 gene and transpositional activity of hobo elements also led to the transgenerational effects of irradiation but only in the F1 offspring. Dysfunction of the genes of other DNA repair systems (mus101 and mus210) showed no visible effects inherited from irradiated parents subjected to hobo transpositions. The mei-41 gene showed specificity in this type of interaction, which consists in its higher efficiency in sensing events induced by transpositional activity rather than irradiation.

scholarly journals Exploiting DNA Endonucleases to Advance Mechanisms of DNA Repair

Biology ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 530
Author(s):  
Marlo K. Thompson ◽  
Robert W. Sobol ◽  
Aishwarya Prakash
Keyword(s):  
Dna Repair ◽  
Mammalian Cells ◽  
Genome Stability ◽  
Gene Editing ◽  
Adaptive Immune System ◽  
Zinc Finger Nucleases ◽  
Specific Gene ◽  
Target Sequence ◽  
Transcription Activator ◽  
Low Cytotoxicity

The earliest methods of genome editing, such as zinc-finger nucleases (ZFN) and transcription activator-like effector nucleases (TALENs), utilize customizable DNA-binding motifs to target the genome at specific loci. While these approaches provided sequence-specific gene-editing capacity, the laborious process of designing and synthesizing recombinant nucleases to recognize a specific target sequence, combined with limited target choices and poor editing efficiency, ultimately minimized the broad utility of these systems. The discovery of clustered regularly interspaced short palindromic repeat sequences (CRISPR) in Escherichia coli dates to 1987, yet it was another 20 years before CRISPR and the CRISPR-associated (Cas) proteins were identified as part of the microbial adaptive immune system, by targeting phage DNA, to fight bacteriophage reinfection. By 2013, CRISPR/Cas9 systems had been engineered to allow gene editing in mammalian cells. The ease of design, low cytotoxicity, and increased efficiency have made CRISPR/Cas9 and its related systems the designer nucleases of choice for many. In this review, we discuss the various CRISPR systems and their broad utility in genome manipulation. We will explore how CRISPR-controlled modifications have advanced our understanding of the mechanisms of genome stability, using the modulation of DNA repair genes as examples.

scholarly journals Coexistence of SOS-Dependent and SOS-Independent Regulation of DNA Repair Genes in Radiation-Resistant Deinococcus Bacteria

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 924
Author(s):  
Laurence Blanchard ◽  
Arjan de Groot
Keyword(s):  
Dna Repair ◽  
Deinococcus Radiodurans ◽  
Dna Repair Genes ◽  
Lesion Bypass ◽  
Radiation Resistant ◽  
Radiation Induced ◽  
Induced Mutagenesis ◽  
High Doses ◽  
Translesion Polymerases ◽  
Repair Genes

Deinococcus bacteria are extremely resistant to radiation and able to repair a shattered genome in an essentially error-free manner after exposure to high doses of radiation or prolonged desiccation. An efficient, SOS-independent response mechanism to induce various DNA repair genes such as recA is essential for radiation resistance. This pathway, called radiation/desiccation response, is controlled by metallopeptidase IrrE and repressor DdrO that are highly conserved in Deinococcus. Among various Deinococcus species, Deinococcus radiodurans has been studied most extensively. Its genome encodes classical DNA repair proteins for error-free repair but no error-prone translesion DNA polymerases, which may suggest that absence of mutagenic lesion bypass is crucial for error-free repair of massive DNA damage. However, many other radiation-resistant Deinococcus species do possess translesion polymerases, and radiation-induced mutagenesis has been demonstrated. At least dozens of Deinococcus species contain a mutagenesis cassette, and some even two cassettes, encoding error-prone translesion polymerase DnaE2 and two other proteins, ImuY and ImuB-C, that are probable accessory factors required for DnaE2 activity. Expression of this mutagenesis cassette is under control of the SOS regulators RecA and LexA. In this paper, we review both the RecA/LexA-controlled mutagenesis and the IrrE/DdrO-controlled radiation/desiccation response in Deinococcus.

scholarly journals CRISPR-Associated Primase-Polymerases are implicated in prokaryotic CRISPR-Cas adaptation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Katerina Zabrady ◽  
Matej Zabrady ◽  
Peter Kolesar ◽  
Arthur W. H. Li ◽  
Aidan J. Doherty
Keyword(s):  
Dna Repair ◽  
Dna Synthesis ◽  
Genome Stability ◽  
Dna Polymerases ◽  
Acquired Immunity ◽  
Strand Displacement ◽  
Genetic Studies ◽  
Type Iiia ◽  
Maintain Genome Stability ◽  
Cas Proteins

AbstractCRISPR-Cas pathways provide prokaryotes with acquired “immunity” against foreign genetic elements, including phages and plasmids. Although many of the proteins associated with CRISPR-Cas mechanisms are characterized, some requisite enzymes remain elusive. Genetic studies have implicated host DNA polymerases in some CRISPR-Cas systems but CRISPR-specific replicases have not yet been discovered. We have identified and characterised a family of CRISPR-Associated Primase-Polymerases (CAPPs) in a range of prokaryotes that are operonically associated with Cas1 and Cas2. CAPPs belong to the Primase-Polymerase (Prim-Pol) superfamily of replicases that operate in various DNA repair and replication pathways that maintain genome stability. Here, we characterise the DNA synthesis activities of bacterial CAPP homologues from Type IIIA and IIIB CRISPR-Cas systems and establish that they possess a range of replicase activities including DNA priming, polymerisation and strand-displacement. We demonstrate that CAPPs operonically-associated partners, Cas1 and Cas2, form a complex that possesses spacer integration activity. We show that CAPPs physically associate with the Cas proteins to form bespoke CRISPR-Cas complexes. Finally, we propose how CAPPs activities, in conjunction with their partners, may function to undertake key roles in CRISPR-Cas adaptation.

scholarly journals NME3 Regulates Mitochondria to Reduce ROS-Mediated Genome Instability

2020 ◽  
Vol 21 (14) ◽  
pp. 5048
Author(s):  
Chih-Wei Chen ◽  
Ning Tsao ◽  
Wei Zhang ◽  
Zee-Fen Chang
Keyword(s):  
Oxidative Stress ◽  
Dna Repair ◽  
Genome Stability ◽  
Nuclear Dna ◽  
Genome Instability ◽  
Mitochondrial Fission ◽  
Nucleoside Diphosphate Kinase ◽  
Mitochondrial Fusion ◽  
Mitochondrial Outer Membrane ◽  
Mitochondrial Oxidative Stress

NME3 is a member of the nucleoside diphosphate kinase (NDPK) family that binds to the mitochondrial outer membrane to stimulate mitochondrial fusion. In this study, we showed that NME3 knockdown delayed DNA repair without reducing the cellular levels of nucleotide triphosphates. Further analyses revealed that NME3 knockdown increased fragmentation of mitochondria, which in turn led to mitochondrial oxidative stress-mediated DNA single-strand breaks (SSBs) in nuclear DNA. Re-expression of wild-type NME3 or inhibition of mitochondrial fission markedly reduced SSBs and facilitated DNA repair in NME3 knockdown cells, while expression of N-terminal deleted mutant defective in mitochondrial binding had no rescue effect. We further showed that disruption of mitochondrial fusion by knockdown of NME4 or MFN1 also caused mitochondrial oxidative stress-mediated genome instability. In conclusion, the contribution of NME3 to redox-regulated genome stability lies in its function in mitochondrial fusion.

Communication of Radiation-Induced Signals in Vivo between DNA Repair Deficient and Proficient Medaka (Oryzias latipes)

2009 ◽  
Vol 43 (9) ◽  
pp. 3335-3342 ◽  
Author(s):  
C. Mothersill ◽  
R. W. Smith ◽  
T. G. Hinton ◽  
K. Aizawa ◽  
C. B. Seymour
Keyword(s):  
Dna Repair ◽  
Oryzias Latipes ◽  
Radiation Induced

scholarly journals Mechanistic Modelling of DNA Repair and Cellular Survival Following Radiation-Induced DNA Damage

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Stephen J. McMahon ◽  
Jan Schuemann ◽  
Harald Paganetti ◽  
Kevin M. Prise
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Mechanistic Modelling ◽  
Cellular Survival ◽  
Radiation Induced

scholarly journals Recent Advances in Understanding Werner Syndrome

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1779 ◽  
Author(s):  
Raghavendra A. Shamanna ◽  
Deborah L. Croteau ◽  
Jong-Hyuk Lee ◽  
Vilhelm A. Bohr
Keyword(s):  
Dna Repair ◽  
Stem Cell ◽  
Genome Stability ◽  
Werner Syndrome ◽  
Genetic Disorder ◽  
Accelerated Aging ◽  
Nutrient Sensing ◽  
Telomere Maintenance ◽  
Telomere Attrition ◽  
Recent Advances

Aging, the universal phenomenon, affects human health and is the primary risk factor for major disease pathologies. Progeroid diseases, which mimic aging at an accelerated rate, have provided cues in understanding the hallmarks of aging. Mutations in DNA repair genes as well as in telomerase subunits are known to cause progeroid syndromes. Werner syndrome (WS), which is characterized by accelerated aging, is an autosomal-recessive genetic disorder. Hallmarks that define the aging process include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulation of nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. WS recapitulates these hallmarks of aging and shows increased incidence and early onset of specific cancers. Genome integrity and stability ensure the normal functioning of the cell and are mainly guarded by the DNA repair machinery and telomeres. WRN, being a RecQ helicase, protects genome stability by regulating DNA repair pathways and telomeres. Recent advances in WS research have elucidated WRN’s role in DNA repair pathway choice regulation, telomere maintenance, resolution of complex DNA structures, epigenetic regulation, and stem cell maintenance.

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