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Brazilian Journal of Medical and... 2024Innate immune system activation is crucial in the inflammatory response, but uncontrolled activation can lead to autoimmune diseases. Cellular exhaustion and senescence... (Review)
Review
Innate immune system activation is crucial in the inflammatory response, but uncontrolled activation can lead to autoimmune diseases. Cellular exhaustion and senescence are two processes that contribute to innate immune tolerance breakdown. Exhausted immune cells are unable to respond adequately to specific antigens or stimuli, while senescent cells have impaired DNA replication and metabolic changes. These processes can impair immune system function and disrupt homeostasis, leading to the emergence of autoimmunity. However, the influence of innate immune exhaustion and senescence on autoimmune disorders is not well understood. This review aims to describe the current findings on the role of innate immune exhaustion and senescence in autoimmunity, focusing on the cellular and molecular changes involved in each process. Specifically, the article explores the markers and pathways associated with immune exhaustion, such as PD-1 and TIM-3, and senescence, including Β-galactosidase (β-GAL), lamin B1, and p16ink4a, and their impact on autoimmune diseases, namely type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, and immune-mediated myopathies. Understanding the mechanisms underlying innate immune exhaustion and senescence in autoimmunity may provide insights for the development of novel therapeutic strategies.
Topics: Humans; Immunity, Innate; Autoimmune Diseases; Cellular Senescence; Autoimmunity; Immune System Exhaustion
PubMed: 38896644
DOI: 10.1590/1414-431X2024e13225 -
ELife Jun 2024ASARs are a family of very-long noncoding RNAs that control replication timing on individual human autosomes, and are essential for chromosome stability. The eight known...
ASARs are a family of very-long noncoding RNAs that control replication timing on individual human autosomes, and are essential for chromosome stability. The eight known ASAR lncRNAs remain closely associated with their parent chromosomes. Analysis of RNA-protein interaction data (from ENCODE) revealed numerous RBPs with significant interactions with multiple ASAR lncRNAs, with several hnRNPs as abundant interactors. An ~7 kb domain within the lncRNA shows a striking density of RBP interaction sites. Genetic deletion and ectopic integration assays indicate that this ~7 kb RNA binding protein domain contains functional sequences for controlling replication timing of entire chromosomes in cis. shRNA-mediated depletion of 10 different RNA binding proteins, including HNRNPA1, HNRNPC, HNRNPL, HNRNPM, HNRNPU, or HNRNPUL1, results in dissociation of ASAR lncRNAs from their chromosome territories, and disrupts the synchronous replication that occurs on all autosome pairs, recapitulating the effect of individual ASAR knockouts on a genome-wide scale. Our results further demonstrate the role that ASARs play during the temporal order of genome-wide replication, and we propose that ASARs function as essential RNA scaffolds for the assembly of hnRNP complexes that help maintain the structural integrity of each mammalian chromosome.
Topics: RNA, Long Noncoding; Humans; Heterogeneous-Nuclear Ribonucleoproteins; DNA Replication Timing; Protein Binding; RNA-Binding Proteins
PubMed: 38896448
DOI: 10.7554/eLife.95898 -
Journal of Clinical Immunology Jun 2024A cell's ability to survive and to evade cancer is contingent on its ability to retain genomic integrity, which can be seriously compromised when nucleic acid...
A cell's ability to survive and to evade cancer is contingent on its ability to retain genomic integrity, which can be seriously compromised when nucleic acid phosphodiester bonds are disrupted. DNA Ligase 1 (LIG1) plays a key role in genome maintenance by sealing single-stranded nicks that are produced during DNA replication and repair. Autosomal recessive mutations in a limited number of individuals have been previously described for this gene. Here we report a homozygous LIG1 mutation (p.A624T), affecting a universally conserved residue, in a patient presenting with leukopenia, neutropenia, lymphopenia, pan-hypogammaglobulinemia, and diminished in vitro response to mitogen stimulation. Patient fibroblasts expressed normal levels of LIG1 protein but exhibited impaired growth, poor viability, high baseline levels of gamma-H2AX foci, and an enhanced susceptibility to DNA-damaging agents. The mutation reduced LIG1 activity by lowering its affinity for magnesium 2.5-fold. Remarkably, it also increased LIG1 fidelity > 50-fold against 3' end 8-Oxoguanine mismatches, exhibiting a marked reduction in its ability to process such nicks. This is expected to yield increased ss- and dsDNA breaks. Molecular dynamic simulations, and Residue Interaction Network studies, predicted an allosteric effect for this mutation on the protein loops associated with the LIG1 high-fidelity magnesium, as well as on DNA binding within the adenylation domain. These dual alterations of suppressed activity and enhanced fidelity, arising from a single mutation, underscore the mechanistic picture of how a LIG1 defect can lead to severe immunological disease.
Topics: Female; Humans; Male; DNA Ligase ATP; Fibroblasts; Homozygote; Molecular Dynamics Simulation; Mutation; Severe Combined Immunodeficiency; Infant
PubMed: 38896336
DOI: 10.1007/s10875-024-01754-1 -
BioRxiv : the Preprint Server For... Jun 2024All bacteria encode a multifunctional DNA-binding protein, DnaA, which initiates chromosomal replication. Despite having the most complex, segmented bacterial genome,...
All bacteria encode a multifunctional DNA-binding protein, DnaA, which initiates chromosomal replication. Despite having the most complex, segmented bacterial genome, little is known about DnaA and its role in maintaining the spirochete's physiology. We utilized inducible CRISPR-interference and overexpression to modulate cellular levels of DnaA to better understand this essential protein. Dysregulation of DnaA, either up or down, significantly slowed replication and increased or decreased cell lengths. Using fluorescent microscopy, we found the DnaA CRISPRi mutants had increased numbers of chromosomes with irregular spacing patterns. The DnaA-depleted spirochetes also exhibited a significant defect in helical morphology. RNA-seq of the conditional mutants showed significant changes in the levels of transcripts involved with flagellar synthesis, elongation, cell division, virulence, and other functions. These findings demonstrate that the DnaA plays a commanding role in maintaining borrelial growth dynamics and protein expression, which are essential for the survival of the Lyme disease spirochete.
PubMed: 38895450
DOI: 10.1101/2024.06.08.598065 -
BioRxiv : the Preprint Server For... Jun 2024In most eukaryotes, mitochondrial organelles contain their own genome, usually circular, which is the remnant of the genome of the ancestral bacterial endosymbiont that...
In most eukaryotes, mitochondrial organelles contain their own genome, usually circular, which is the remnant of the genome of the ancestral bacterial endosymbiont that gave rise to modern mitochondria. Mitochondrial genomes are dramatically reduced in their gene content due to the process of endosymbiotic gene transfer to the nucleus; as a result most mitochondrial proteins are encoded in the nucleus and imported into mitochondria. This includes the components of the dedicated mitochondrial transcription and replication systems and regulatory factors, which are entirely distinct from the information processing systems in the nucleus. However, since the 1990s several nuclear transcription factors have been reported to act in mitochondria, and previously we identified 8 human and 3 mouse transcription factors (TFs) with strong localized enrichment over the mitochondrial genome using ChIP-seq (Chromatin Immunoprecipitation) datasets from the second phase of the ENCODE (Encyclopedia of DNA Elements) Project Consortium. Here, we analyze the greatly expanded in the intervening decade ENCODE compendium of TF ChIP-seq datasets (a total of 6,153 ChIP experiments for 942 proteins, of which 763 are sequence-specific TFs) combined with interpretative deep learning models of TF occupancy to create a comprehensive compendium of nuclear TFs that show evidence of association with the mitochondrial genome. We find some evidence for chrM occupancy for 50 nuclear TFs and two other proteins, with bZIP TFs emerging as most likely to be playing a role in mitochondria. However, we also observe that in cases where the same TF has been assayed with multiple antibodies and ChIP protocols, evidence for its chrM occupancy is not always reproducible. In the light of these findings, we discuss the evidential criteria for establishing chrM occupancy and reevaluate the overall compendium of putative mitochondrial-acting nuclear TFs.
PubMed: 38895386
DOI: 10.1101/2024.06.04.597442 -
Frontiers in Oncology 2024Approximately 50% of tubo-ovarian high-grade serous carcinomas (HGSCs) have functional homologous recombination-mediated (HR) DNA repair, so-called HR-proficient tumors,... (Review)
Review
Approximately 50% of tubo-ovarian high-grade serous carcinomas (HGSCs) have functional homologous recombination-mediated (HR) DNA repair, so-called HR-proficient tumors, which are often associated with primary platinum resistance (relapse within six months after completion of first-line therapy), minimal benefit from poly(ADP-ribose) polymerase (PARP) inhibitors, and shorter survival. HR-proficient tumors comprise multiple molecular subtypes including cases with amplification, amplification or alteration, and are often characterized as "cold" tumors with fewer infiltrating lymphocytes and decreased expression of PD-1/PD-L1. Several new treatment approaches aim to manipulate these negative prognostic features and render HR-proficient tumors more susceptible to treatment. Alterations in multiple different molecules and pathways in the DNA damage response are driving new drug development to target HR-proficient cancer cells, such as inhibitors of the CDK or P13K/AKT pathways, as well as ATR inhibitors. Treatment combinations with chemotherapy or PARP inhibitors and agents targeting DNA replication stress have shown promising preclinical and clinical results. New approaches in immunotherapy are also being explored, including vaccines or antibody drug conjugates. Many approaches are still in the early stages of development and further clinical trials will determine their clinical relevance. There is a need to include HR-proficient tumors in ovarian cancer trials and to analyze them in a more targeted manner to provide further evidence for their specific therapy, as this will be crucial in improving the overall prognosis of HGSC and ovarian cancer in general.
PubMed: 38894867
DOI: 10.3389/fonc.2024.1387281 -
International Journal of Molecular... Jun 2024Asexual development is the main propagation and transmission mode of and the basis of its pathogenicity. The regulation mechanism of conidiation and the key gene...
Asexual development is the main propagation and transmission mode of and the basis of its pathogenicity. The regulation mechanism of conidiation and the key gene resources for utilization are key links to improving the conidia yield and quality of . Their clarification may promote the industrialization of fungal pesticides. Here, we compared the regulation of morphology, resistance to external stress, virulence, and nutrient utilization capacity between the upstream developmental regulatory gene and the key genes , , and in the central growth and development pathway. The results showed that the Δ and Δ mutants completely lost the capacity to conidiate and that the Δ mutant had seriously reduced conidiation capacity. Although the deletion of did not reduce the conidiation ability as much as deletions of , , and , it significantly reduced the fungal response to external stress, virulence, and nutrient utilization, while the deletion of the three other genes had little effect. Via transcriptome analysis and screening the yeast nuclear system library, we found that the differentially expressed genes in the Δ mutants were concentrated in the signaling pathways of ABC transporters, propionate metabolism, tryptophan metabolism, DNA replication, mismatch repair, and fatty acid metabolism. FluG directly acted on 40 proteins that were involved in various signaling pathways such as metabolism, oxidative stress, and cell homeostasis. The analysis indicated that the regulatory function of was mainly involved in DNA replication, cell homeostasis, fungal growth and metabolism, and the response to external stress. Our results revealed the biological function of in asexual development and the responses to several environmental stresses as well as its influence on the asexual development regulatory network in .
Topics: Beauveria; Gene Expression Regulation, Fungal; Fungal Proteins; Reproduction, Asexual; Spores, Fungal; Virulence; Gene Expression Profiling; Stress, Physiological; Transcriptome
PubMed: 38892450
DOI: 10.3390/ijms25116261 -
International Journal of Molecular... May 2024Recently, a compound derived from recent scientific advances named has emerged as the focus of this research, the aim of which is to explore its potential impact on...
Recently, a compound derived from recent scientific advances named has emerged as the focus of this research, the aim of which is to explore its potential impact on solid tumor cell lines. Using a combination of bioinformatics and biological assays, this study conducted an in-depth investigation of the effects of . The results of this study have substantial implications for cancer research and treatment. has shown remarkable efficacy in inhibiting the growth of several cancer cell lines, including those representing prostate carcinoma (PC3) and cervical carcinoma (HeLa). The high sensitivity of these cells, indicated by low IC values, underscores its potential as a promising chemotherapeutic agent. In addition, has revealed the ability to induce cell cycle arrest, particularly in the G2/M phase, a phenomenon with critical implications for tumor initiation and growth. By interfering with DNA replication in cancer cells, has shown the capacity to trigger cell death, offering a new avenue for cancer treatment. In addition, computational analyses have identified key genes affected by treatment, suggesting potential therapeutic targets. These genes are involved in critical biological processes, including cell cycle regulation, DNA replication and microtubule dynamics, all of which are central to cancer development and progression. In conclusion, this study highlights the different mechanisms of that inhibit cancer cell growth and alter the cell cycle. These promising results suggest the potential for more effective and less toxic anticancer therapies. Further in vivo validation and exploration of combination therapies are critical to improve cancer treatment outcomes.
Topics: Humans; Microtubules; Antineoplastic Agents; Cell Line, Tumor; Acrylonitrile; Cell Proliferation; Neoplasms; HeLa Cells; Apoptosis; Triazoles; Cell Cycle Checkpoints; Tubulin Modulators; PC-3 Cells
PubMed: 38891892
DOI: 10.3390/ijms25115704 -
International Journal of Molecular... May 2024In this review we examine the functionally diverse ATPase associated with various cellular activities (AAA-ATPase), valosin-containing protein (VCP/p97), its molecular... (Review)
Review
In this review we examine the functionally diverse ATPase associated with various cellular activities (AAA-ATPase), valosin-containing protein (VCP/p97), its molecular functions, the mutational landscape of VCP and the phenotypic manifestation of VCP disease. VCP is crucial to a multitude of cellular functions including protein quality control, endoplasmic reticulum-associated degradation (ERAD), autophagy, mitophagy, lysophagy, stress granule formation and clearance, DNA replication and mitosis, DNA damage response including nucleotide excision repair, ATM- and ATR-mediated damage response, homologous repair and non-homologous end joining. VCP variants cause multisystem proteinopathy, and pathology can arise in several tissue types such as skeletal muscle, bone, brain, motor neurons, sensory neurons and possibly cardiac muscle, with the disease course being challenging to predict.
Topics: Valosin Containing Protein; Humans; Phenotype; Animals; Mutation; Autophagy; DNA Repair
PubMed: 38891822
DOI: 10.3390/ijms25115633 -
Cells May 2024Telomeres, potential biomarkers of aging, are known to shorten with continued cigarette smoke exposure. In order to further investigate this process and its impact on...
Telomeres, potential biomarkers of aging, are known to shorten with continued cigarette smoke exposure. In order to further investigate this process and its impact on cellular stress and inflammation, we used an in vitro model with cigarette smoke extract (CSE) and observed the downregulation of telomere stabilizing and genes after CSE treatment. is a subunit of telomerase and a well-known oncogenic marker, which is overexpressed in over 85% of cancers and may contribute to lung cancer development in smokers. We also observed an increase in and expression levels after CSE treatment, as well as increased protein levels revealed by immunohistochemical staining in smokers' lung tissue samples compared to non-smokers. The effects of overexpression were further studied by quantifying , an inflammatory protein induced by , which showed greater upregulation in smokers compared to non-smokers. Similar changes in gene expression patterns for , , , and were observed in blood and buccal swab samples from smokers compared to non-smokers. The results from this study provide insight into the mechanisms behind smoking causing telomere shortening and how this may contribute to the induction of inflammation and/or tumorigenesis, which may lead to comorbidities in smokers.
Topics: Humans; Inflammation; Aging; Telomeric Repeat Binding Protein 2; Shelterin Complex; Cytokines; Telomere; Telomerase; Smoking; Ubiquitins; Telomere-Binding Proteins; Interferon-gamma; Telomere Homeostasis; Male; Telomere Shortening; Female; Middle Aged
PubMed: 38891017
DOI: 10.3390/cells13110884