scholarly journals Transcription-coupled DNA repair underlies variation in persister awakening and the emergence of resistance

2021 ◽  
Author(s):  
Dorien Wilmaerts ◽  
Charline Focant ◽  
Paul Matthay ◽  
Jan Michiels
Keyword(s):  
Mutation Rate ◽  
Oxidative Dna Damage ◽  
Bacterial Population ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Cellular Damage ◽  
Resistance Development ◽  
Nucleotide Excision ◽  
Molecular Factor ◽  
Emergence Of Resistance

Persisters constitute a population of temporarily antibiotic-tolerant variants in an isogenic bacterial population and are considered an important cause of relapsing infections. It is currently unclear how cellular damage inflicted by antibiotic action is reversed upon persister state exit and how this relates to antibiotic resistance development. We demonstrate that persisters, upon fluoroquinolone treatment, accumulate oxidative damage which is repaired through nucleotide excision repair. Detection of the damage occurs via transcription-coupled repair using UvrD-mediated backtracking or Mfd-mediated displacement of the RNA polymerase. This competition results in heterogeneity in persister awakening lags. Most persisters repair the oxidative DNA damage, displaying a mutation rate equal to the untreated population. However, the promutagenic factor Mfd increases the mutation rate in a persister subpopulation. Our data provide in-depth insight in the molecular mechanisms underlying persister survival and pinpoints Mfd as an important molecular factor linking persistence to resistance development.

scholarly journals A frameshift mutation is repaired through nonsense-mediated gene revising in E. coli

2016 ◽  
Author(s):  
Xiaolong Wang ◽  
Xuxiang Wang ◽  
Chunyan Li ◽  
Haibo Peng ◽  
Yalei Wang ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Mismatch Repair ◽  
Rna Editing ◽  
Mutation Rate ◽  
Molecular Mechanisms ◽  
Frameshift Mutation ◽  
Excision Repair ◽  
Gene Repair ◽  
E Coli ◽  
Nucleotide Excision

AbstractThe molecular mechanisms for repairing DNA damages and point mutations have been well understood but it remains unclear how a frameshift mutation is repaired. Here we report that frameshift reversion occurs in E. coli more frequently than expected and appears to be a targeted gene repair signaled by premature termination codons (PTCs), producing high-level variations in the repaired genes. Genome resequencing shows that the revertant genome is highly stable, and the single-molecule variations in the repaired genes are derived from RNA editing. A multi-omics analysis shows that the expression levels change greatly in most the DNA and RNA manipulating genes. DNA replication, transcription, RNA editing, RNA degradation, nucleotide excision repair, mismatch repair, and homologous recombination were upregulated in the frameshift or revertant, but the base excision repair was not. Moreover, genes and transposons in a duplicate region silenced in wild type E. coli were activated in the frameshift. Finally, we propose a nonsense-mediated gene revising (NMGR) model for frame repair, which also acts as a driving force for molecular evolution. In essence, nonsense mRNAs are recognized, edited, and transported to template the repair of the coding gene by RNA-directed DNA repair, nucleotide excision, mismatch repair, and homologous recombination. Thanks to NMGR, the mutation rate temporarily rises in a frameshift gene, bringing genetic diversity while repairing the frameshift mutation and accelerating the evolution process without a high mutation rate in the genome.

scholarly journals Nucleotide excision repair is impaired by binding of transcription factors to DNA

2015 ◽  
Author(s):  
Radhakrishnan Sabarinathan ◽  
Loris Mularoni ◽  
Jordi Deu-Pons ◽  
Abel Gonzalez-Perez ◽  
Nuria Lopez-Bigas
Keyword(s):  
Nucleotide Excision Repair ◽  
Mutation Rate ◽  
Binding Sites ◽  
Somatic Mutations ◽  
Excision Repair ◽  
Replication Timing ◽  
Driver Mutations ◽  
Cancer Driver ◽  
Nucleotide Excision ◽  
Active Transcription

Somatic mutations are the driving force of cancer genome evolution. The rate of somatic mutations appears in great variability across the genome due to chromatin organization, DNA accessibility and replication timing. However, other variables that may influence the mutation rate locally, such as DNA-binding proteins, are unknown. Here we demonstrate that the rate of somatic mutations in melanoma tumors is highly increased at active Transcription Factor binding sites (TFBS) and nucleosome embedded DNA, compared to their flanking regions. Using recently available excision-repair sequencing (XR-seq) data, we show that the higher mutation rate at these sites is caused by a decrease of the levels of nucleotide excision repair (NER) activity. Therefore, our work demonstrates that DNA-bound proteins interfere with the NER machinery, which results in an increased rate of mutations at their binding sites. This finding has important implications in our understanding of mutational and DNA repair processes and in the identification of cancer driver mutations.

scholarly journals Molecular Mechanisms of H. pylori-Induced DNA Double-Strand Breaks

2018 ◽  
Vol 19 (10) ◽  
pp. 2891 ◽  
Author(s):  
Dawit Kidane
Keyword(s):  
Genomic Instability ◽  
Oxidative Dna Damage ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Current Knowledge ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
Double Strand Breaks ◽  
Strand Breaks ◽  
H Pylori

Infections contribute to carcinogenesis through inflammation-related mechanisms. H. pylori infection is a significant risk factor for gastric carcinogenesis. However, the molecular mechanism by which H. pylori infection contributes to carcinogenesis has not been fully elucidated. H. pylori-associated chronic inflammation is linked to genomic instability via reactive oxygen and nitrogen species (RONS). In this article, we summarize the current knowledge of H. pylori-induced double strand breaks (DSBs). Furthermore, we provide mechanistic insight into how processing of oxidative DNA damage via base excision repair (BER) leads to DSBs. We review recent studies on how H. pylori infection triggers NF-κB/inducible NO synthase (iNOS) versus NF-κB/nucleotide excision repair (NER) axis-mediated DSBs to drive genomic instability. This review discusses current research findings that are related to mechanisms of DSBs and repair during H. pylori infection.

scholarly journals Oxidative DNA Damage and Nucleotide Excision Repair

2013 ◽  
Vol 18 (18) ◽  
pp. 2409-2419 ◽  
Author(s):  
Joost P.M. Melis ◽  
Harry van Steeg ◽  
Mirjam Luijten
Keyword(s):  
Dna Damage ◽  
Nucleotide Excision Repair ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Nucleotide Excision

scholarly journals A Tn-seq screen of Streptococcus pneumoniae uncovers DNA repair as the major pathway for desiccation tolerance and transmission

2021 ◽  
Author(s):  
Allison J. Matthews ◽  
Hannah M. Rowe ◽  
Jason W. Rosch ◽  
Andrew Camilli
Keyword(s):  
Dna Repair ◽  
Streptococcus Pneumoniae ◽  
Nucleotide Excision Repair ◽  
Desiccation Tolerance ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Opportunistic Pathogen ◽  
Repair Gene ◽  
Major Pathway ◽  
Nucleotide Excision

Streptococcus pneumoniae is an opportunistic pathogen that is a common cause of serious invasive diseases such as pneumonia, bacteremia, meningitis, and otitis media. Transmission of this bacterium has classically been thought to occur through inhalation of respiratory droplets and direct contact with nasal secretions. However, the demonstration that S. pneumoniae is desiccation tolerant, and therefore environmentally stable for extended periods of time, opens up the possibility that this pathogen is also transmitted via contaminated surfaces (fomites). To better understand the molecular mechanisms that enable S. pneumoniae to survive periods of desiccation, we performed a high-throughput transposon sequencing (Tn-seq) screen in search of genetic determinants of desiccation tolerance. We identified 42 genes whose disruption reduced desiccation tolerance, and 45 genes that enhanced desiccation tolerance. The nucleotide excision repair pathway was the most enriched category in our Tn-seq results, and we found that additional DNA repair pathways are required for desiccation tolerance, demonstrating the importance of maintaining genome integrity after desiccation. Deletion of the nucleotide excision repair gene uvrA resulted in a delay in transmission between infant mice, indicating a correlation between desiccation tolerance and pneumococcal transmission. Understanding the molecular mechanisms that enable pneumococcal persistence in the environment may enable targeting of these pathways to prevent fomite transmission, thereby preventing the establishment of new colonization and any resulting invasive disease.

scholarly journals The involvement of nucleotide excision repair proteins in the removal of oxidative DNA damage

2020 ◽  
Vol 48 (20) ◽  
pp. 11227-11243 ◽  
Author(s):  
Namrata Kumar ◽  
Sripriya Raja ◽  
Bennett Van Houten
Keyword(s):  
Nucleotide Excision Repair ◽  
Base Excision Repair ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Base Damage ◽  
The Past ◽  
Nucleotide Excision ◽  
Oxidative Processes ◽  
Repair Pathways ◽  
Base Excision

Abstract The six major mammalian DNA repair pathways were discovered as independent processes, each dedicated to remove specific types of lesions, but the past two decades have brought into focus the significant interplay between these pathways. In particular, several studies have demonstrated that certain proteins of the nucleotide excision repair (NER) and base excision repair (BER) pathways work in a cooperative manner in the removal of oxidative lesions. This review focuses on recent data showing how the NER proteins, XPA, XPC, XPG, CSA, CSB and UV-DDB, work to stimulate known glycosylases involved in the removal of certain forms of base damage resulting from oxidative processes, and also discusses how some oxidative lesions are probably directly repaired through NER. Finally, since many glycosylases are inhibited from working on damage in the context of chromatin, we detail how we believe UV-DDB may be the first responder in altering the structure of damage containing-nucleosomes, allowing access to BER enzymes.

Role of H3K18ac-regulated nucleotide excision repair-related genes in arsenic-induced DNA damage and repair of HaCaT cells

2020 ◽  
Vol 39 (9) ◽  
pp. 1168-1177 ◽  
Author(s):  
AL Zhang ◽  
L Chen ◽  
L Ma ◽  
XJ Ding ◽  
SF Tang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nucleotide Excision Repair ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
The Body ◽  
Hacat Cells ◽  
Transcriptional Expression ◽  
Promoter Regions ◽  
Nucleotide Excision

Arsenic is an environmental poison and is a grade I human carcinogen that can cause many types of damage to the body. The skin is one of the main target organs of arsenic damage, but the molecular mechanisms underlying arsenic poisoning are not clear. Arsenic is an epigenetic agent. Histone acetylation is one of the earliest covalent modifications to be discovered and is closely related to the occurrence and development of tumors. To investigate the role of acetylated histone H3K18 (H3K18 ac) in arsenic-induced DNA damage, HaCaT cells were exposed to sodium arsenite (NaAsO2) for 24 h. It was found that arsenic induced the downregulation of xeroderma pigmentosum A, D, and F ( XPA, XPD, and XPF—nucleotide excision repair (NER)-related genes) expression, as well as histone H3K18 ac expression, and aggravated DNA damage. Chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR) analysis showed that H3K18 acetylation in the promoter regions of XPA, XPD, and XPF was downregulated. In addition, the use of the histone deacetylase inhibitor trichostatin A (TSA) partially inhibited arsenic-induced DNA damage, inhibited deacetylation of H3K18 ac in the promoter regions of XPA, XPD, and XPF genes, increased acetylation of H3K18, and promoted the transcriptional expression of NER-related genes. Our study revealed that NaAsO2 induces DNA damage and inhibits the expression of NER-related genes, while TSA increases the H3K18 ac enrichment level and promotes the transcriptional expression of NER, thereby inhibiting DNA damage. These findings provide new ideas for understanding the molecular mechanisms underlying arsenic-induced skin damage.

Molecular Mechanisms of Mammalian Global Genome Nucleotide Excision Repair

2006 ◽  
Vol 106 (2) ◽  
pp. 253-276 ◽  
Author(s):  
Ludovic C. J. Gillet ◽  
Orlando D. Schärer
Keyword(s):  
Nucleotide Excision Repair ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Nucleotide Excision
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