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CNS Neuroscience & Therapeutics Mar 2024With the widespread prevalence of neurodegenerative diseases (NDs) and high rates of mortality and disability, it is imminent to find accurate targets for intervention.... (Review)
Review
BACKGROUND
With the widespread prevalence of neurodegenerative diseases (NDs) and high rates of mortality and disability, it is imminent to find accurate targets for intervention. There is growing evidence that neuroimmunity is pivotal in the pathology of NDs and that interventions targeting neuroimmunity hold great promise. Exogenous or dislocated nucleic acids activate the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS), activating the stimulator of interferon genes (STING). The activated STING triggers innate immune responses and then the cGAS-STING signaling pathway links abnormal nucleic acid sensing to the immune response. Recently, numerous studies have shown that neuroinflammation regulated by cGAS-STING signaling plays an essential role in NDs.
AIMS
In this review, we summarized the mechanism of cGAS-STING signaling in NDs and focused on inhibitors targeting cGAS-STING.
CONCLUSION
The cGAS-STING signaling plays an important role in the pathogenesis of NDs. Inhibiting the cGAS-STING signaling may provide new measures in the treatment of NDs.
Topics: Humans; DNA; Immunity, Innate; Neurodegenerative Diseases; Nucleotidyltransferases; Signal Transduction
PubMed: 38459658
DOI: 10.1111/cns.14671 -
Biosensors Oct 2023An advanced, cost-effective, and portable DNA biosensor capable of detecting multiple bacteria simultaneously has been developed. The biosensor comprises a fast and...
An advanced, cost-effective, and portable DNA biosensor capable of detecting multiple bacteria simultaneously has been developed. The biosensor comprises a fast and inexpensive potentiostat that controls the applied potential to a screen-printed electrochemical array platform functionalized with MoS flakes and bacterial DNA probes. The current response obtained by thionine functionalized carbon nanodots (Ty-CDs) is monitored as an electrochemical indicator of the hybridization event. The design of the potentiostat prioritizes achieving an optimal signal-to-noise ratio and incorporates a user-friendly interface compatible with various devices, including computers, mobile phones, and tablets. The device is compact, lightweight, and manufactured at a low cost. The key components of the potentiostat include a data acquisition board capable of analyzing multiple samples simultaneously and a controller board. The results of this study confirm the ability of the multiplex portable biosensor to successfully detect specific bacterial DNA sequences, demonstrating its reliability and superior performance compared with a traditional, more complex, and laboratory-oriented potentiostat.
Topics: DNA, Bacterial; Reproducibility of Results; DNA; Bacteria; Biosensing Techniques; Electrochemical Techniques
PubMed: 37998133
DOI: 10.3390/bios13110958 -
EMBO Reports Dec 2023Double-strand breaks (DSBs) are the most harmful DNA lesions, with a strong impact on cell proliferation and genome integrity. Depending on cell cycle stage, DSBs are... (Review)
Review
Double-strand breaks (DSBs) are the most harmful DNA lesions, with a strong impact on cell proliferation and genome integrity. Depending on cell cycle stage, DSBs are preferentially repaired by non-homologous end joining or homologous recombination (HR). In recent years, numerous reports have revealed that DSBs enhance DNA-RNA hybrid formation around the break site. We call these hybrids "break-induced RNA-DNA hybrids" (BIRDHs) to differentiate them from sporadic R-loops consisting of DNA-RNA hybrids and a displaced single-strand DNA occurring co-transcriptionally in intact DNA. Here, we review and discuss the most relevant data about BIRDHs, with a focus on two main questions raised: (i) whether BIRDHs form by de novo transcription after a DSB or by a pre-existing nascent RNA in DNA regions undergoing transcription and (ii) whether they have a positive role in HR or are just obstacles to HR accidentally generated as an intrinsic risk of transcription. We aim to provide a comprehensive view of the exciting and yet unresolved questions about the source and impact of BIRDHs in the cell.
Topics: RNA; DNA Breaks, Double-Stranded; Homologous Recombination; DNA Repair; DNA; DNA End-Joining Repair
PubMed: 37818834
DOI: 10.15252/embr.202357801 -
Current Opinion in Structural Biology Feb 2024Eukaryotic transcription factors activate gene expression with their DNA-binding domains and activation domains. DNA-binding domains bind the genome by recognizing... (Review)
Review
Eukaryotic transcription factors activate gene expression with their DNA-binding domains and activation domains. DNA-binding domains bind the genome by recognizing structurally related DNA sequences; they are structured, conserved, and predictable from protein sequences. Activation domains recruit chromatin modifiers, coactivator complexes, or basal transcriptional machinery via structurally diverse protein-protein interactions. Activation domains and DNA-binding domains have been called independent, modular units, but there are many departures from modularity, including interactions between these regions and overlap in function. Compared to DNA-binding domains, activation domains are poorly understood because they are poorly conserved, intrinsically disordered, and difficult to predict from protein sequences. This review, organized around commonly asked questions, describes recent progress that the field has made in understanding the sequence features that control activation domains and predicting them from sequence.
Topics: Transcriptional Activation; Protein Binding; Transcription Factors; Protein Domains; DNA
PubMed: 38056064
DOI: 10.1016/j.sbi.2023.102732 -
Genes Mar 2024The polymerase chain reaction (PCR) has played a fundamental role in our understanding of the world, and has applications across a broad range of disciplines. The... (Review)
Review
The polymerase chain reaction (PCR) has played a fundamental role in our understanding of the world, and has applications across a broad range of disciplines. The introduction of PCR into forensic science marked the beginning of a new era of DNA profiling. This era has pushed PCR to its limits and allowed genetic data to be generated from trace DNA. Trace samples contain very small amounts of degraded DNA associated with inhibitory compounds and ions. Despite significant development in the PCR process since it was first introduced, the challenges of profiling inhibited and degraded samples remain. This review examines the evolution of the PCR from its inception in the 1980s, through to its current application in forensic science. The driving factors behind PCR evolution for DNA profiling are discussed along with a critical comparison of cycling conditions used in commercial PCR kits. Newer PCR methods that are currently used in forensic practice and beyond are examined, and possible future directions of PCR for DNA profiling are evaluated.
Topics: Humans; Polymerase Chain Reaction; Forensic Sciences; DNA Fingerprinting; DNA; Forensic Genetics
PubMed: 38674373
DOI: 10.3390/genes15040438 -
DNA Repair Oct 2023DNA double-stranded breaks (DSBs) are a particularly challenging form of DNA damage to repair because the damaged DNA must not only undergo the chemical reactions...
DNA double-stranded breaks (DSBs) are a particularly challenging form of DNA damage to repair because the damaged DNA must not only undergo the chemical reactions responsible for returning it to its original state, but, additionally, the two free ends can become physically separated in the nucleus and must be bridged prior to repair. In nonhomologous end joining (NHEJ), one of the major pathways of DSB repair, repair is carried out by a number of repair factors capable of binding to and directly joining DNA ends. It has been unclear how these processes are carried out at a molecular level, owing in part to the lack of structural evidence describing the coordination of the NHEJ factors with each other and a DNA substrate. Advances in cryo-Electron Microscopy (cryo-EM), allowing for the structural characterization of large protein complexes that would be intractable using other techniques, have led to the visualization several key steps of the NHEJ process, which support a model of sequential assembly of repair factors at the DSB, followed by end-bridging mediated by protein-protein complexes and transition to full synapsis. Here we examine the structural evidence for these models, devoting particular attention to recent work identifying a new NHEJ intermediate state and incorporating new NHEJ factors into the general mechanism. We also discuss the evolving understanding of end-bridging mechanisms in NHEJ and DNA-PKcs's role in mediating DSB repair.
Topics: Cryoelectron Microscopy; DNA End-Joining Repair; DNA Repair; DNA Breaks, Double-Stranded; DNA
PubMed: 37556875
DOI: 10.1016/j.dnarep.2023.103547 -
Cancer Biology & Medicine Sep 2023
Topics: Humans; DNA Repair; DNA Breaks, Double-Stranded; DNA
PubMed: 37731219
DOI: 10.20892/j.issn.2095-3941.2023.0252 -
Science Advances Apr 2024Molecular strain can be introduced to influence the outcome of chemical reactions. Once a thermodynamic product is formed, however, reversing the course of a...
Molecular strain can be introduced to influence the outcome of chemical reactions. Once a thermodynamic product is formed, however, reversing the course of a strain-promoted reaction is challenging. Here, a reversible, strain-promoted polymerization in cyclic DNA is reported. The use of nonhybridizing, single-stranded spacers as short as a single nucleotide in length can promote DNA cyclization. Molecular strain is generated by duplexing the spacers, leading to ring opening and subsequent polymerization. Then, removal of the strain-generating duplexers triggers depolymerization and cyclic dimer recovery via enthalpy-driven cyclization and entropy-mediated ring contraction. This reversibility is retained even when a protein is conjugated to the DNA strands, and the architecture of the protein assemblies can be modulated between bivalent and polyvalent states. This work underscores the utility of using DNA not only as a programmable ligand for assembly but also as a route to access restorable bonds, thus providing a molecular basis for DNA-based materials with shape-memory, self-healing, and stimuli-responsive properties.
Topics: Polymerization; DNA; Cyclization; Thermodynamics; Nucleic Acid Conformation
PubMed: 38657068
DOI: 10.1126/sciadv.ado8020 -
The FEBS Journal Sep 2023RNA polymerase II moves along genes to decode genetic information stored in the mammalian genome into messenger RNA and different forms of non-coding RNA. However, the... (Review)
Review
RNA polymerase II moves along genes to decode genetic information stored in the mammalian genome into messenger RNA and different forms of non-coding RNA. However, the transcription process is frequently challenged by DNA lesions caused by exogenous and endogenous insults, among which helix-distorting DNA lesions and double-stranded DNA breaks are particularly harmful for cell survival. In response to such DNA damage, RNA polymerase II transcription is regulated both locally and globally by multi-layer mechanisms, whereas transcription-blocking lesions are repaired before transcription can recover. Failure in DNA damage repair will cause genome instability and cell death. Although recent studies have expanded our understanding of RNA polymerase II regulation confronting DNA lesions, it is still not always clear what the direct contribution of RNA polymerase II is in the DNA damage repair processes. In this review, we focus on how RNA polymerase II and transcription are both repressed by transcription stalling lesions such as DNA-adducts and double strand breaks, as well as how they are actively regulated to support the cellular response to DNA damage and favour the repair of lesions.
Topics: Animals; RNA Polymerase II; Transcription, Genetic; DNA Repair; DNA Damage; DNA; Mammals
PubMed: 35731652
DOI: 10.1111/febs.16561 -
Nature Nanotechnology Nov 2023Means to analyse cellular proteins and their millions of variants at the single-molecule level would uncover substantial information previously unknown to biology....
Means to analyse cellular proteins and their millions of variants at the single-molecule level would uncover substantial information previously unknown to biology. Nanopore technology, which underpins long-read DNA and RNA sequencing, holds potential for full-length proteoform identification. We use electro-osmosis in an engineered charge-selective nanopore for the non-enzymatic capture, unfolding and translocation of individual polypeptides of more than 1,200 residues. Unlabelled thioredoxin polyproteins undergo transport through the nanopore, with directional co-translocational unfolding occurring unit by unit from either the C or N terminus. Chaotropic reagents at non-denaturing concentrations accelerate the analysis. By monitoring the ionic current flowing through the nanopore, we locate post-translational modifications deep within the polypeptide chains, laying the groundwork for compiling inventories of the proteoforms in cells and tissues.
Topics: Nanopores; Peptides; Protein Processing, Post-Translational; DNA
PubMed: 37500774
DOI: 10.1038/s41565-023-01462-8