scholarly journals A C. elegans model for neurodegeneration in Cockayne syndrome

2020 ◽  
Vol 48 (19) ◽  
pp. 10973-10985
Author(s):  
Amanda F C Lopes ◽  
Katarzyna Bozek ◽  
Marija Herholz ◽  
Aleksandra Trifunovic ◽  
Matthias Rieckher ◽  
...  
Keyword(s):  
Dna Damage ◽  
Respiratory Activity ◽  
Cockayne Syndrome ◽  
Driving Factor ◽  
C Elegans ◽  
Progressive Neurodegeneration ◽  
Congenital Syndrome ◽  
Live Organism

Abstract Cockayne syndrome (CS) is a congenital syndrome characterized by growth and mental retardation, and premature ageing. The complexity of CS and mammalian models warrants simpler metazoan models that display CS-like phenotypes that could be studied in the context of a live organism. Here, we provide a characterization of neuronal and mitochondrial aberrations caused by a mutation in the csb-1 gene in Caenorhabditis elegans. We report a progressive neurodegeneration in adult animals that is enhanced upon UV-induced DNA damage. The csb-1 mutants show dysfunctional hyperfused mitochondria that degrade upon DNA damage, resulting in diminished respiratory activity. Our data support the role of endogenous DNA damage as a driving factor of CS-related neuropathology and underline the role of mitochondrial dysfunction in the disease.

scholarly journals Characterization of Caenorhabditis elegans Homologs of the Down Syndrome Candidate Gene DYRK1A

Genetics ◽  
2003 ◽  
Vol 163 (2) ◽  
pp. 571-580 ◽  
Author(s):  
William B Raich ◽  
Celine Moorman ◽  
Clay O Lacefield ◽  
Jonah Lehrer ◽  
Dusan Bartsch ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Caenorhabditis Elegans ◽  
Trisomy 21 ◽  
Gene Dosage ◽  
Inducible Promoters ◽  
C Elegans ◽  
Dual Specificity ◽  
Specificity Protein

Abstract The pathology of trisomy 21/Down syndrome includes cognitive and memory deficits. Increased expression of the dual-specificity protein kinase DYRK1A kinase (DYRK1A) appears to play a significant role in the neuropathology of Down syndrome. To shed light on the cellular role of DYRK1A and related genes we identified three DYRK/minibrain-like genes in the genome sequence of Caenorhabditis elegans, termed mbk-1, mbk-2, and hpk-1. We found these genes to be widely expressed and to localize to distinct subcellular compartments. We isolated deletion alleles in all three genes and show that loss of mbk-1, the gene most closely related to DYRK1A, causes no obvious defects, while another gene, mbk-2, is essential for viability. The overexpression of DYRK1A in Down syndrome led us to examine the effects of overexpression of its C. elegans ortholog mbk-1. We found that animals containing additional copies of the mbk-1 gene display behavioral defects in chemotaxis toward volatile chemoattractants and that the extent of these defects correlates with mbk-1 gene dosage. Using tissue-specific and inducible promoters, we show that additional copies of mbk-1 can impair olfaction cell-autonomously in mature, fully differentiated neurons and that this impairment is reversible. Our results suggest that increased gene dosage of human DYRK1A in trisomy 21 may disrupt the function of fully differentiated neurons and that this disruption is reversible.

AMPK blocks chromatin activation and consequent R-loop formation to protect genome stability following acute starvation

2021 ◽  
Author(s):  
Bing Sun ◽  
McLean Sherrin ◽  
Richard Roy
Keyword(s):  
Dna Damage ◽  
Genome Stability ◽  
Germ Line ◽  
Critical Role ◽  
Significant Proportion ◽  
Loop Formation ◽  
C Elegans ◽  
Chromatin Activation ◽  
Acute Starvation

Abstract During periods of starvation organisms must modify both gene expression and metabolic pathways to adjust to the energy stress. We previously reported that C. elegans that lack AMPK have transgenerational reproductive defects that result from abnormally elevated H3K4me3 levels in the germ line following recovery from acute starvation1. Here we show that H3K4me3 is dramatically increased at promoters, driving aberrant transcription elongation that results in the accumulation of R-loops in the starved AMPK mutants. DRIP-seq analysis demonstrated that a significant proportion of the genome was affected by R-loop formation with a dramatic expansion in the number of R-loops at numerous loci, most pronounced at the promoter-TSS regions of genes in the starved AMPK mutants. The R-loops are transmissible into subsequent generations, likely contributing to the transgenerational reproductive defects typical of these mutants following starvation. Strikingly, AMPK null germ lines show considerably more RAD-51 foci at sites of R-loop formation, potentially sequestering it from its critical role at meiotic breaks and/or at sites of induced DNA damage. Our study reveals a previously unforeseen role of AMPK in maintaining genome stability following starvation, where in its absence R-loops accumulate, resulting in reproductive compromise and DNA damage hypersensitivity.

Genes necessary for C. elegans cell and growth cone migrations

Development ◽  
1997 ◽  
Vol 124 (9) ◽  
pp. 1831-1843 ◽  
Author(s):  
W.C. Forrester ◽  
G. Garriga
Keyword(s):  
Cell Fate ◽  
Single Gene ◽  
Growth Cones ◽  
Cell Fate Specification ◽  
Fate Specification ◽  
C Elegans ◽  
Final Destination ◽  
Multiple Cell

The migrations of cells and growth cones contribute to form and pattern during metazoan development. To study the mechanisms that regulate cell motility, we have screened for C. elegans mutants defective in the posteriorly directed migrations of the canal-associated neurons (CANs). Here we describe 14 genes necessary for CAN cell migration. Our characterization of the mutants has led to three conclusions. First, the mutations define three gene classes: genes necessary for cell fate specification, genes necessary for multiple cell migrations and a single gene necessary for final positioning of migrating cells. Second, cell interactions between the CAN and HSN, a neuron that migrates anteriorly to a position adjacent to the CAN, control the final destination of the HSN cell body. Third, C. elegans larval development requires the CANs. In the absence of CAN function, larvae arrest development, with excess fluid accumulating in their pseudocoeloms. This phenotype may reflect a role of the CANs in osmoregulation.

scholarly journals A role for Rab5 in structuring the endoplasmic reticulum

2007 ◽  
Vol 178 (1) ◽  
pp. 43-56 ◽  
Author(s):  
Anjon Audhya ◽  
Arshad Desai ◽  
Karen Oegema
Keyword(s):  
Endoplasmic Reticulum ◽  
Caenorhabditis Elegans ◽  
Nuclear Envelope ◽  
Rab Gtpases ◽  
C Elegans ◽  
Rab Family ◽  
Kinetics Of

The endoplasmic reticulum (ER) is a contiguous network of interconnected membrane sheets and tubules. The ER is differentiated into distinct domains, including the peripheral ER and nuclear envelope. Inhibition of two ER proteins, Rtn4a and DP1/NogoA, was previously shown to inhibit the formation of ER tubules in vitro. We show that the formation of ER tubules in vitro also requires a Rab family GTPase. Characterization of the 29 Caenorhabditis elegans Rab GTPases reveals that depletion of RAB-5 phenocopies the defects in peripheral ER structure that result from depletion of RET-1 and YOP-1, the C. elegans homologues of Rtn4a and DP1/NogoA. Perturbation of endocytosis by other means did not affect ER structure; the role of RAB-5 in ER morphology is thus independent of its well-studied requirement for endocytosis. RAB-5 and YOP-1/RET-1 also control the kinetics of nuclear envelope disassembly, which suggests an important role for the morphology of the peripheral ER in this process.

scholarly journals Characterization of SMG7 14-3-3-like domain reveals phosphoserine binding-independent regulation of p53 and UPF1

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Lauren E. Cowen ◽  
Hongwei Luo ◽  
Yi Tang
Keyword(s):  
Dna Damage ◽  
Protein Interactions ◽  
Cell Growth Arrest ◽  
Damage Response ◽  
Nonsense Mediated Mrna Decay ◽  
Dependent Cell ◽  
Dependent Protein ◽  
Client Proteins

Abstract The 14-3-3-related protein SMG7 plays critical roles in regulation of DNA damage response and nonsense-mediated mRNA decay (NMD). Like 14-3-3, SMG7 engages phosphoserine-dependent protein interactions; however, the precise role of phosphorylation-mediated SMG7 binding remains unknown. Here, we show that DNA damage-induced SMG7-p53 binding requires phosphorylated Ser15 on p53, and that substitution of the conserved lysine residue K66 in the SMG7 14-3-3-like domain with the glutamic acid (E) abolishes interactions with its client proteins p53 and UPF1. Unexpectedly, loss of phosphoserine-dependent SMG7 binding does not significantly affect p53 stabilization/activation, and p53-dependent cell growth arrest or apoptosis upon DNA damage. Also surprisingly, cells expressing the SMG7 K66E-knockin mutant retain fully functional UPF1-mediated NMD. These findings are highly unusual, given that phosphorylation-mediated 14-3-3 binding has essential roles in numerous cellular signaling pathways. Thus, our studies suggest that 14-3-3-like proteins such as SMG7 likely function using additional distinct regulatory mechanisms besides phosphoserine-mediated protein interactions.

scholarly journals Cooperation of the Cockayne Syndrome Group B Protein and Poly(ADP-Ribose) Polymerase 1 in the Response to Oxidative Stress

2005 ◽  
Vol 25 (17) ◽  
pp. 7625-7636 ◽  
Author(s):  
Tina Thorslund ◽  
Cayetano von Kobbe ◽  
Jeanine A. Harrigan ◽  
Fred E. Indig ◽  
Mette Christiansen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cellular Response ◽  
Genetic Disorder ◽  
Cockayne Syndrome ◽  
Dna Lesions ◽  
Dna Breaks ◽  
Group B ◽  
Parp 1

ABSTRACT Cockayne syndrome (CS) is a rare genetic disorder characterized as a segmental premature-aging syndrome. The CS group B (CSB) protein has previously been implicated in transcription-coupled repair, transcriptional elongation, and restoration of RNA synthesis after DNA damage. Recently, evidence for a role of CSB in base excision repair of oxidative DNA lesions has accumulated. In our search to understand the molecular function of CSB in this process, we identify a physical and functional interaction between CSB and poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 is a nuclear enzyme that protects the integrity of the genome by responding to oxidative DNA damage and facilitating DNA repair. PARP-1 binds to single-strand DNA breaks which activate the catalytic ability of PARP-1 to add polymers of ADP-ribose to various proteins. We find that CSB is present at sites of activated PARP-1 after oxidative stress, identify CSB as a new substrate of PARP-1, and demonstrate that poly(ADP-ribosyl)ation of CSB inhibits its DNA-dependent ATPase activity. Furthermore, we find that CSB-deficient cell lines are hypersensitive to inhibition of PARP. Our results implicate CSB in the PARP-1 poly(ADP-ribosyl)ation response after oxidative stress and thus suggest a novel role of CSB in the cellular response to oxidative damage.

scholarly journals Characterization of the role of a trimeric protein phosphatase complex in recovery from cisplatin-induced versus noncrosslinking DNA damage

FEBS Journal ◽  
2008 ◽  
Vol 275 (16) ◽  
pp. 4211-4221 ◽  
Author(s):  
Cristina Vázquez-Martin ◽  
John Rouse ◽  
Patricia T. W. Cohen
Keyword(s):  
Dna Damage ◽  
Protein Phosphatase

Abstracts of a joint meeting of the Association of Clinical Oral Microbiologists and the Biofilm Club held at the Eastman Dental Institute, University College London on 2 March 2004

Biofilms ◽  
2004 ◽  
Vol 1 (2) ◽  
pp. 139-145
Keyword(s):  
Infection Control ◽  
Infection Model ◽  
Periodontal Pathogens ◽  
C Elegans ◽  
University College London ◽  
Dental Unit Waterlines ◽  
Dental Setting ◽  
Antimicrobial Biomaterials

Principles of antimicrobial biomaterials: why they do not (usually) workCharacterization of bacterial adhesion onto surfaces of stainless steel by micromanipulationYersinia spp./C. elegans infection model: biofilms on a biotic surfacePeriodontal pathogens in dental unit waterlinesBiofilms as reservoirs of antibiotic resistanceSystemic antimicrobials and periodontitis – a classic biofilm diseasePrion disease in the dental settingReviewing the role of biofilms in infection controlInfection control in dental technology laboratoriesReview of the treatment aspects of dental unit water systems

scholarly journals Characterization of SID-1-dependent and independent intergenerational RNA transport pathways in Caenorhabditis elegans

2017 ◽  
Author(s):  
Eddie Wang ◽  
Craig P. Hunter
Keyword(s):  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Epigenetic Inheritance ◽  
Transport Pathways ◽  
C Elegans ◽  
Early Embryos ◽  
Systemic Rna

AbstractSystemic RNA interference (RNAi) in C. elegans is dependent on sid-1 (Winstonet al. 2002), sid-3 (Joseet al. 2012) and sid-5 (Hinaset al. 2012). After injection, expression, or ingestion, double-stranded RNA (dsRNA) is transported between cells throughout the animal to enable RNAi in most tissues, including the germline and progeny. Here, we characterize the role of the Sid genes in transport of dsRNA to progeny. We previously reported that dsRNA injected directly in the germline unexpectedly requires sid-1 activity in the progeny to initiate RNAi (Winstonet al. 2002). We now show that germline injected dsRNA can travel by three independent pathways to silence gene expression in embryos. First, germline injected dsRNA is delivered, presumably by bulk flow, into oocytes and embryos. This means of delivery, which does not require sid-1, is limited by the amount and location of injected dsRNA. Second, maternal sid-1 transports extracellular dsRNA into the germline where it can silence maternal deposited mRNAs and segregate to embryos to silence embryonically expressed mRNAs. Third, extracellular dsRNA is also endocytosed into oocytes by the low-density lipoprotein (LDL) receptor superfamily homolog RME-2. The endocytosed dsRNA then requires sid-1 and sid-5 in embryos to silence embryonically expressed genes. Extracellular fluorescent dsRNA, once endocytosed into oocytes, does not co-localize with VIT2::GFP and it does not require sid-1 activity to segregate from the late endocytosis marker GFP::RAB-7 in early embryos. In conclusion, we identify genes and pathways that function redundantly for intergenerational RNA transfer that may represent mechanisms for transgenerational epigenetic inheritance.

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