2024

The white gene as a transgenesis marker for the cricket Gryllus bimaculatus: Author(s) : Gonzalez-Sqalli E, Caron M, Loppin B,; Journal : G3: Genes, Genomes, Genetics; 2024; Abstract The cricket Gryllus bimaculatus is an emerging model insect of the order Orthoptera that is used in a wide variety of biological research themes. This hemimetabolous species appears highly complementary to Drosophila and other well-established holometabolous models. To improve transgenesis applications in G. bimaculatus, we have designed a transformation marker gene inspired from the widespread Drosophila mini-white+. Using CRISPR/Cas9, we first generated a loss-of-function mutant allele of the Gb-white gene (Gb-w), which exhibits a white eye coloration at all developmental stages. We then demonstrate that transgenic insertions of a piggyBac vector containing a 3xP3-Gb-w+ cassette rescue eye pigmentation. As an application, we used this vector to generate G. bimaculatus lines expressing a centromeric histone H3 variant (CenH3.1) fused to EGFP and validated EGFP-CenH3.1 detection at cricket centromeres. Finally, we demonstrate that Minos-based germline transformation and site-specific plasmid insertion with the ΦC31 integrase system function in G. bimaculatus.
Deciphering Molecular Mechanisms Involved in the Modulation of Human Aquaporins' Water Permeability by Zinc Cations: A Molecular Dynamics Approach.: Author(s) : Mom R, Réty S, Mocquet V, Auguin D,; Journal : Int J Mol Sci; 2024; Aquaporins (AQPs) constitute a wide family of water channels implicated in allkind of physiological processes. Zinc is the second most abundant trace elementin the human body and a few studies have highlighted regulation of AQP0 and AQP4by zinc. In the present work, we addressed the putative regulation of AQPs byzinc cations in silico through molecular dynamics simulations of human AQP0,AQP2, AQP4, and AQP5. Our results align with other scales of study and several invitro techniques, hence strengthening the reliability of this regulation by zinc.We also described two distinct putative molecular mechanisms associated with theincrease or decrease in AQPs' water permeability after zinc binding. Inassociation with other studies, our work will help deciphering the interactionnetworks existing between zinc and channel proteins.
Retinal atrophy, inflammation, phagocytic and metabolic disruptions develop in the MerTK-cleavage-resistant mouse model.: Author(s) : Enderlin J, Rieu Q, Réty S, Vanoni E, Roux S, Dégardin J, César Q, Augustin S, Nous C, Cai B, Fontaine V, Sennlaub F, Nandrot E,; Journal : Front Neurosci; 2024; In the eye, cells from the retinal pigment epithelium (RPE) facing theneurosensory retina exert several functions that are all crucial for long-termsurvival of photoreceptors (PRs) and vision. Among those, RPE cells phagocytoseunder a circadian rhythm photoreceptor outer segment (POS) tips that areconstantly subjected to light rays and oxidative attacks. The MerTK tyrosinekinase receptor is a key element of this phagocytic machinery required for POSinternalization. Recently, we showed that MerTK is subjected to the cleavage ofits extracellular domain to finely control its function. In addition, monocytesin retinal blood vessels can migrate inside the inner retina and differentiateinto macrophages expressing MerTK, but their role in this context has not beenstudied yet. We thus investigated the ocular phenotype of MerTKcleavage-resistant (MerTK(CR)) mice to understand the relevance of thischaracteristic on retinal homeostasis at the RPE and macrophage levels. MerTK(CR)retinae appear to develop and function normally, as observed in retinal sections,by electroretinogram recordings and optokinetic behavioral tests. Monitoring ofMerTK(CR) and control mice between the ages of 3 and 18 months showed thedevelopment of large degenerative areas in the central retina as early as 4months when followed monthly by optical coherence tomography (OCT) plus fundusphotography (FP)/autofluorescence (AF) detection but not by OCT alone. Thedegenerative areas were associated with AF, which seems to be due to infiltratedmacrophages, as observed by OCT and histology. MerTK(CR) RPE primary culturesphagocytosed less POS in vitro, while in vivo, the circadian rhythm of POSphagocytosis was deregulated. Mitochondrial function and energy production werereduced in freshly dissected RPE/choroid tissues at all ages, thus showing ametabolic impairment not present in macrophages. RPE anomalies were detected byelectron microscopy, including phagosomes retained in the apical area andvacuoles. Altogether, this new mouse model displays a novel phenotype that couldprove useful to understanding the interplay between RPE and PRs in inflammatoryretinal degenerations and highlights new roles for MerTK in the regulation of theenergetic metabolism and the maintenance of the immune privilege in the retina.
Structural insights into the N-terminal APHB domain of HrpA: mediating canonical and i-motif recognition.: Author(s) : Xin B, Huang L, Yuan L, Liu N, Li H, Ai X, Lei D, Hou X, Rety S, Xi X,; Journal : Nucleic Acids Res; 2024; RNA helicases function as versatile enzymes primarily responsible for remodelingRNA secondary structures and organizing ribonucleoprotein complexes. In ourstudy, we conducted a systematic analysis of the helicase-related activities ofEscherichia coli HrpA and presented the structures of both its apo form and itscomplex bound with both conventional and non-canonical DNAs. Our findings revealthat HrpA exhibits NTP hydrolysis activity and binds to ssDNA and ssRNA indistinct sequence-dependent manners. While the helicase core plays an essentialrole in unwinding RNA/RNA and RNA/DNA duplexes, the N-terminal extension in HrpA,consisting of three helices referred to as the APHB domain, is crucial for ssDNAbinding and RNA/DNA duplex unwinding. Importantly, the APHB domain is implicatedin binding to non-canonical DNA structures such as G-quadruplex and i-motif, andthis report presents the first solved i-motif-helicase complex. This research notonly provides comprehensive insights into the multifaceted roles of HrpA as anRNA helicase but also establishes a foundation for further investigations intothe recognition and functional implications of i-motif DNA structures in variousbiological processes.
The catalytic triad of rice NARROW LEAF1 involves H234.: Author(s) : Huang L, Liu N, Chen W, Ai X, Li H, Zhang Z, Hou X, Fossé P, Mauffret O, Lei D, Rety S, Xi X,; Journal : Nat Plants; 2024; NARROW LEAF1 (NAL1) exerts a multifaceted influence on leaf morphology and cropyield. Recent crystal study proposed that histidine 233 (H233) is part of thecatalytic triad. Here we report that unlike suggested previously, H234 instead ofH233 is a component of the catalytic triad alongside residues D291 and S385 inNAL1. Remarkably, residue 233 unexpectedly plays a pivotal role in regulatingNAL1's proteolytic activity. These findings establish a strong foundation forutilizing NAL1 in breeding programs aimed at improving crop yield.
Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite opposite effects in heart contraction.: Author(s) : Auguin D, Robert-Paganin J, Réty S, Kikuti C, David A, Theumer G, Schmidt A, Knölker H, Houdusse A,; Journal : Nat Commun; 2024; Inherited cardiomyopathies are common cardiac diseases worldwide, leading in thelate stage to heart failure and death. The most promising treatments againstthese diseases are small molecules directly modulating the force produced byβ-cardiac myosin, the molecular motor driving heart contraction. Omecamtivmecarbil and Mavacamten are two such molecules that completed phase 3 clinicaltrials, and the inhibitor Mavacamten is now approved by the FDA. In contrast toMavacamten, Omecamtiv mecarbil acts as an activator of cardiac contractility.Here, we reveal by X-ray crystallography that both drugs target the same pocketand stabilize a pre-stroke structural state, with only few local differences.All-atom molecular dynamics simulations reveal how these molecules producedistinct effects in motor allostery thus impacting force production in oppositeway. Altogether, our results provide the framework for rational drug developmentfor the purpose of personalized medicine.
Stimulation of ATP Hydrolysis by ssDNA Provides the Necessary Mechanochemical Energy for G4 Unfolding.: Author(s) : Dai Y, Duan X, Fu W, Wang S, Liu N, Li H, Ai X, Guo H, Navés C, Bugnard E, Auguin D, Hou X, Rety S, Xi X,; Journal : J Mol Biol; 2024; The G-quadruplex (G4) is a distinct geometric and electrophysical structurecompared to classical double-stranded DNA, and its stability can impede essentialcellular processes such as replication, transcription, and translation. Thisstudy focuses on the BsPif1 helicase, revealing its ability to bind independentlyto both single-stranded DNA (ssDNA) and G4 structures. The unfolding activity ofBsPif1 on G4 relies on the presence of a single tail chain, and the covalentcontinuity between the single tail chain and the G4's main chain is necessary forefficient G4 unwinding. This suggests that ATP hydrolysis-driven ssDNAtranslocation exerts a pull force on G4 unwinding. Molecular dynamics simulationsidentified a specific region within BsPif1 that contains five crucial amino acidsites responsible for G4 binding and unwinding. A "molecular wire stripper" modelis proposed to explain BsPif1's mechanism of G4 unwinding. These findings providea new theoretical foundation for further exploration of the G4 developmentmechanism in Pif1 family helicases.
Aquaporin Modulation by Cations, a Review.: Author(s) : Mom R, Mocquet V, Auguin D, Réty S,; Journal : Curr Issues Mol Biol; 2024; Aquaporins (AQPs) are transmembrane channels initially discovered for their rolein water flux facilitation through biological membranes. Over the years, a muchmore complex and subtle picture of these channels appeared, highlighting manyother solutes accommodated by AQPs and a dense regulatory network finely tuningcell membranes' water permeability. At the intersection between severaltransduction pathways (e.g., cell volume regulation, calcium signaling, potassiumcycling, etc.), this wide and ancient protein family is considered an importanttherapeutic target for cancer treatment and many other pathophysiologies.However, a precise and isoform-specific modulation of these channels function isstill challenging. Among the modulators of AQPs functions, cations have beenshown to play a significant contribution, starting with mercury beinghistorically associated with the inhibition of AQPs since their discovery. Whilethe comprehension of AQPs modulation by cations has improved, a unifyingmolecular mechanism integrating all current knowledge is still lacking. In aneffort to extract general trends, we reviewed all known modulations of AQPs bycations to capture a first glimpse of this regulatory network. We paid particularattention to the associated molecular mechanisms and pinpointed the residuesinvolved in cation binding and in conformational changes tied up to themodulation of the channel function.
Plasticity and environment-specific relationships between gene expression and fitness in Saccharomyces cerevisiae.: Author(s) : Siddiq M, Duveau F, Wittkopp P,; Journal : Nat Ecol Evol; 2024; The environment influences how an organism's genotype determines its phenotype and how this phenotype affects its fitness. Here, to better understand this dual role of environment in the production and selection of phenotypic variation, we determined genotype-phenotype-fitness relationships for mutant strains of Saccharomyces cerevisiae in four environments. Specifically, we measured how promoter mutations of the metabolic gene TDH3 modified expression level and affected growth for four different carbon sources. In each environment, we observed a clear relationship between TDH3 expression level and fitness, but this relationship differed among environments. Mutations with similar effects on expression in different environments often had different effects on fitness and vice versa. Such environment-specific relationships between phenotype and fitness can shape the evolution of phenotypic plasticity. We also found that mutations disrupting binding sites for transcription factors had more variable effects on expression among environments than those disrupting the TATA box, which is part of the core promoter. However, mutations with the most environmentally variable effects on fitness were located in the TATA box, because of both the lack of plasticity of TATA box mutations and environment-specific fitness functions. This observation suggests that mutations affecting different molecular mechanisms contribute unequally to regulatory sequence evolution in changing environments.
Condensin loop extrusion properties, roadblocks, and role in homology search in S. cerevisiae: Author(s) : Piveteau V, Salari H, Dumont A, Savocco J, Dupont C, Jost D, Piazza A,; Journal : BioRxiv; 2024; The in vivo mechanism, regulations by cis-acting roadblocks, and biological functions of loop extrusion by eukaryotic SMC complexes are incompletely defined. Here, using Hi-C, we identified two condensin-dependent contact stripes at the Recombination Enhancer (RE) and the rDNA in S. cerevisiae. We show that oriented, unidirectional loop extrusion proceeds from these sites with an estimated processivity ∼170 kb and a density ∼0.04-0.18 that varies across the cell cycle. Centromeres and highly-transcribed RNA PolII-dependent genes are permeable condensin roadblocks. Other positionally labile elements such as replication forks and Smc5/6 complexes bound to substrates generated in the absence of Top2 also hinder loop extrusion by condensin. Cohesin is not an obstacle for condensin. Finally, a DNA double-strand break at MAT blocks condensin, which results in the rapid establishment of a long-range RE-MAT loop that juxtaposes the recombination machinery with its HMLα donor target. Hence, all budding yeast SMCs are involved in recombinational DNA repair. We propose a revised model for donor selection during MAT switching that exploits specific properties of loop extrusion by condensin. It can serve as a paradigm for the establishment of other types of selective interactions along chromosomes.
Space-Scale Hybrid Continuous-Discrete Sliding Frank-Wolfe Method: Author(s) : Lage C, Pustelnik N, Arbona J, Audit B,; Journal : IEEE Signal Processing Letters; 2024
Transcription regulates the spatio-temporal dynamics of genes through micro-compartmentalization.: Author(s) : Salari H, Fourel G, Jost D,; Journal : Nat Commun; 2024; Although our understanding of the involvement of heterochromatin architecturalfactors in shaping nuclear organization is improving, there is still ongoingdebate regarding the role of active genes in this process. In this study, weutilize publicly-available Micro-C data from mouse embryonic stem cells toinvestigate the relationship between gene transcription and 3D gene folding. Ouranalysis uncovers a nonmonotonic - globally positive - correlation betweenintragenic contact density and Pol II occupancy, independent of cohesin-basedloop extrusion. Through the development of a biophysical model integrating therole of transcription dynamics within a polymer model of chromosome organization,we demonstrate that Pol II-mediated attractive interactions with limited valencybetween transcribed regions yield quantitative predictions consistent withchromosome-conformation-capture and live-imaging experiments. Our work providescompelling evidence that transcriptional activity shapes the 4D genome throughPol II-mediated micro-compartmentalization.
Mechanism of homology search expansion during recombinational DNA break repair in Saccharomyces cerevisiae.: Author(s) : Dumont A, Mendiboure N, Savocco J, Anani L, Moreau P, Thierry A, Modolo L, Jost D, Piazza A,; Journal : Mol Cell; 2024; Homology search is a central step of DNA double-strand break (DSB) repair byhomologous recombination (HR). How it operates in cells remains elusive. Wedeveloped a Hi-C-based methodology to map single-stranded DNA (ssDNA) contactsgenome-wide in S. cerevisiae, which revealed two main homology search phases.Initial search conducted by short Rad51-ssDNA nucleoprotein filaments (NPFs) isconfined in cis by cohesin-mediated chromatin loop folding. Progressive growth ofstiff NPFs enables exploration of distant genomic sites. Long-range resectiondrives this transition from local to genome-wide search by increasing theprobability of assembling extensive NPFs. DSB end-tethering promotes coordinatedsearch by opposite NPFs. Finally, an autonomous genetic element on chromosome IIIengages the NPF, which stimulates homology search in its vicinity. This workreveals the mechanism of the progressive expansion of homology search thatis orchestrated by chromatin organizers, long-range resection,end-tethering, and specialized genetic elements and that exploits the stiff NPFstructure conferred by Rad51 oligomerization.
A new type of non-Mendelian segregation.: Author(s) : Blanc C, Delattre M,; Journal : Nat Ecol Evol; 2024
Mechanism of homology search expansion during recombinational DNA break repair in Saccharomyces cerevisiae: Author(s) : Dumont A, Mendiboure N, Savocco J, Modolo L, Jost D, Piazza A,; Journal : Molecular Cell; 2024; Homology search is a central step of DNA double-strand break (DSB) repair by homologous recombination (HR). How it operates in cells remains elusive. We developed a Hi-C-based methodology to map single-stranded DNA (ssDNA) contacts genome-wide in S. cerevisiae, which revealed two main homology search phases. Initial search conducted by short Rad51-ssDNA nucleoprotein filaments (NPFs) is confined in cis by cohesin-mediated chromatin loop folding. Progressive growth of stiff NPFs enables exploration of distant genomic sites. Long-range resection drives this transition from local to genome-wide search by increasing the probability of assembling extensive NPFs. DSB end-tethering promotes coordinated search by opposite NPFs. Finally, an autonomous genetic element on chromosome III engages the NPF, which stimulates homology search in its vicinity. This work reveals the mechanism of the progressive expansion of homology search that is orchestrated by chromatin organizers, long-range resection, end-tethering, and specialized genetic elements and that exploits the stiff NPF structure conferred by Rad51 oligomerization.
The C. elegans SET1 histone methyltransferase SET-2 is not required for transgenerational memory of silencing.: Author(s) : Bedet C, Quarato P, Palladino F, Cecere G, Robert V,; Journal : MicroPubl Biol; 2024; The SET-2 /SET1 histone H3K4 methyltransferase and RNAi pathway components arerequired to maintain fertility across generations in C. elegans . SET-2 preservesthe germline transcriptional program transgenerationally, and RNAi pathways relyon small RNAs to establish and maintain transgenerational gene silencing. Weinvestigated whether the functionality of RNAi-induced transgenerationalsilencing and the composition of pools of endogenous small RNA are affected bythe absence of SET-2 . Our results suggest that defects in RNAi pathways are notresponsible for the transcriptional misregulation observed in the absence ofSET-2 .
AlphaFold2 Predicts Whether Proteins Interact Amidst Confounding Structural Compatibility: Author(s) : Martin J,; Journal : Journal of Chemical Information and Modeling; 2024; Predicting whether two proteins physically interact is one of the holy grails of computational biology, galvanized by rapid advancements in deep learning. AlphaFold2, although not developed with this goal, is promising in this respect. Here, I test the prediction capability of AlphaFold2 on a very challenging data set, where proteins are structurally compatible, even when they do not interact. AlphaFold2 achieves high discrimination between interacting and non-interacting proteins, and the cases of misclassifications can either be rescued by revisiting the input sequences or can suggest false positives and negatives in the data set. AlphaFold2 is thus not impaired by the compatibility between protein structures and has the potential to be applied on a large scale.
Dynamics of Protein–RNA Interfaces Using All-Atom Molecular Dynamics Simulations: Author(s) : Sabei A, Hognon C, Martin J, Frezza E,; Journal : The Journal of Physical Chemistry B; 2024; Facing the current challenges posed by human health diseases requires the understanding of cell machinery at a molecular level. The interplay between proteins and RNA is key for any physiological phenomenon, as well protein–RNA interactions. To understand these interactions, many experimental techniques have been developed, spanning a very wide range of spatial and temporal resolutions. In particular, the knowledge of tridimensional structures of protein–RNA complexes provides structural, mechanical, and dynamical pieces of information essential to understand their functions. To get insights into the dynamics of protein–RNA complexes, we carried out all-atom molecular dynamics simulations in explicit solvent on nine different protein–RNA complexes with different functions and interface size by taking into account the bound and unbound forms. First, we characterized structural changes upon binding and, for the RNA part, the change in the puckering. Second, we extensively analyzed the interfaces, their dynamics and structural properties, and the structural waters involved in the binding, as well as the contacts mediated by them. Based on our analysis, the interfaces rearranged during the simulation time showing alternative and stable residue–residue contacts with respect to the experimental structure.
Ultrastructure Expansion Microscopy applied to C. elegans embryos.: Author(s) : Burdet V, Bournonville L, Das M, Wenger E, Delattre M, Steiner F, Guichard P, Hamel V,; Journal : MicroPubl Biol; 2024; Visualization of organelles using expansion microscopy has been previouslyapplied to Caenorhadbitis elegans adult gonads or worms. However, its applicationto embryos has remained a challenge due to the protective eggshell barrier. Here,by combining freeze-cracking and ultrastructure expansion microscopy (U-ExM), wedemonstrate a four-time isotropic expansion of C. elegans embryos. As an examplestructure, we chose the nuclear pore and demonstrate that we achieve sufficientresolution to distinguish them individually. Our work provides proof of principlefor U-ExM in C. elegans embryos, which will be applicable for imaging a widerange of cellular structures in this model system.
Translation-dependent and -independent mRNA decay occur through mutually exclusive pathways defined by ribosome density during T cell activation.: Author(s) : Mercier B, Labaronne E, Cluet D, Guiguettaz L, Fontrodona N, Bicknell A, Corbin A, Wencker M, Aube F, Modolo L, Jouravleva K, Auboeuf D, Moore M, Ricci E,; Journal : Genome Res; 2024; mRNA translation and decay are tightly interconnected processes both in thecontext of mRNA quality-control pathways and for the degradation of functionalmRNAs. Cotranslational mRNA degradation through codon usage, ribosome collisions,and the recruitment of specific proteins to ribosomes is an important determinantof mRNA turnover. However, the extent to which translation-dependent mRNA decay(TDD) and translation-independent mRNA decay (TID) pathways participate in thedegradation of mRNAs has not been studied yet. Here we describe a comprehensiveanalysis of basal and signal-induced TDD and TID in mouse primary CD4(+) T cells.Our results indicate that most cellular transcripts are decayed to some extent ina translation-dependent manner. Our analysis further identifies the length ofuntranslated regions, the density of ribosomes, and GC3 content as importantdeterminants of TDD magnitude. Consistently, all transcripts that undergo changesin ribosome density within their coding sequence upon T cell activation display acorresponding change in their TDD level. Moreover, we reveal a dynamic modulationin the relationship between GC3 content and TDD upon T cell activation, with areversal in the impact of GC3- and AU3-rich codons. Altogether, our data show astrong and dynamic interconnection between mRNA translation and decay inmammalian primary cells.
Stable structures or PABP1 loading protects cellular and viral RNAs against ISG20-mediated decay.: Author(s) : Louvat C, Deymier S, Nguyen X, Labaronne E, Noy K, Cariou M, Corbin A, Mateo M, Ricci E, Fiorini F, Cimarelli A,; Journal : Life Sci Alliance; 2024; ISG20 is an IFN-induced 3'-5' RNA exonuclease that acts as a broad antiviralfactor. At present, the features that expose RNA to ISG20 remain unclear,although recent studies have pointed to the modulatory role of epitranscriptomicmodifications in the susceptibility of target RNAs to ISG20. These findings raisethe question as to how cellular RNAs, on which these modifications are abundant,cope with ISG20. To obtain an unbiased perspective on this topic, we used RNA-seqand biochemical assays to identify elements that regulate the behavior of RNAsagainst ISG20. RNA-seq analyses not only indicate a general preservation of thecell transcriptome, but they also highlight a small, but detectable, decrease inthe levels of histone mRNAs. Contrarily to all other cellular ones, histone mRNAsare non-polyadenylated and possess a short stem-loop at their 3' end, promptingus to examine the relationship between these features and ISG20 degradation. Theresults we have obtained indicate that poly(A)-binding protein loading on the RNA3' tail provides a primal protection against ISG20, easily explaining the overallprotection of cellular mRNAs observed by RNA-seq. Terminal stem-loop RNAstructures have been associated with ISG20 protection before. Here, were-examined this question and found that the balance between resistance andsusceptibility to ISG20 depends on their thermodynamic stability. These resultsshed new light on the complex interplay that regulates the susceptibility ofdifferent classes of viruses against ISG20.
Metabolism-dependent secondary effect of anti-MAPK cancer therapy on DNA repair.: Author(s) : Aubé F, Fontrodona N, Guiguettaz L, Vallin E, Fabbri L, Lapendry A, Vagner S, Ricci E, Auboeuf D,; Journal : NAR Cancer; 2024; Amino acid bioavailability impacts mRNA translation in a codon-dependent manner.Here, we report that the anti-cancer MAPK inhibitors (MAPKi) decrease theintracellular concentration of aspartate and glutamate in melanoma cells. Thiscoincides with the accumulation of ribosomes on codons corresponding to theseamino acids and triggers the translation-dependent degradation of mRNAs encodingaspartate- and glutamate-rich proteins, involved in DNA metabolism such as DNAreplication and repair. Consequently, cells that survive MAPKi degrade aspartateand glutamate likely to generate energy, which simultaneously decreases theirrequirement for amino acids due to the downregulation of aspartate- andglutamate-rich proteins involved in cell proliferation. Concomitantly, thedownregulation of aspartate- and glutamate-rich proteins involved in DNA repairincreases DNA damage loads. Thus, DNA repair defects, and therefore mutations,are at least in part a secondary effect of the metabolic adaptation of cellsexposed to MAPKi.
SIN-3 transcriptional coregulator maintains mitochondrial homeostasis and polyamine flux: Author(s) : Giovannetti M, Rodríguez-Palero M, Fabrizio P, Nicolle O, Bedet C, Michaux G, Witting M, Artal-Sanz M, Palladino F,; Journal : iScience; 2024; Summary Mitochondrial function relies on the coordinated transcription of mitochondrial and nuclear genomes to assemble respiratory chain complexes. Across species, the SIN3 coregulator influences mitochondrial functions, but how its loss impacts mitochondrial homeostasis and metabolism in the context of a whole organism is unknown. Exploring this link is important because SIN3 haploinsufficiency causes intellectual disability/autism syndromes and SIN3 plays a role in tumor biology. Here we show that loss of C. elegans SIN-3 results in transcriptional deregulation of mitochondrial- and nuclear-encoded mitochondrial genes, potentially leading to mito-nuclear imbalance. Consistent with impaired mitochondrial function, sin-3 mutants show extensive mitochondrial fragmentation by transmission electron microscopy (TEM) and in vivo imaging, and altered oxygen consumption. Metabolomic analysis of sin-3 mutant animals revealed a mitochondria stress signature and deregulation of methionine flux, resulting in decreased S-adenosyl methionine (SAM) and increased polyamine levels. Our results identify SIN3 as a key regulator of mitochondrial dynamics and metabolic flux, with important implications for human pathologies.
Yeast cell responses and survival during periodic osmotic stress are controlled by glucose availability: Author(s) : Duveau F, Cordier C, Chiron L, Le Bec M, Pouzet S, Seguin J, Llamosi A, Sorre B, Di Meglio J, Hersen P,; Journal : Elife; 2024; Natural environments of living organisms are often dynamic and multifactorial, with multiple parameters fluctuating over time. To better understand how cells respond to dynamically interacting factors, we quantified the effects of dual fluctuations of osmotic stress and glucose deprivation on yeast cells using microfluidics and time-lapse microscopy. Strikingly, we observed that cell proliferation, survival, and signaling depend on the phasing of the two periodic stresses. Cells divided faster, survived longer, and showed decreased transcriptional response when fluctuations of hyperosmotic stress and glucose deprivation occurred in phase than when the two stresses occurred alternatively. Therefore, glucose availability regulates yeast responses to dynamic osmotic stress, showcasing the key role of metabolic fluctuations in cellular responses to dynamic stress. We also found that mutants with impaired osmotic stress response were better adapted to alternating stresses than wild-type cells, showing that genetic mechanisms of adaptation to a persistent stress factor can be detrimental under dynamically interacting conditions.
RNAP II antagonizes mitotic chromatin folding and chromosome segregation by condensin.: Author(s) : Lebreton J, Colin L, Chatre E, Bernard P,; Journal : Cell Rep; 2024; Condensin shapes mitotic chromosomes by folding chromatin into loops, but whetherit does so by DNA-loop extrusion remains speculative. Although loop-extrudingcohesin is stalled by transcription, the impact of transcription on condensin,which is enriched at highly expressed genes in many species, remains unclear.Using degrons of Rpb1 or the torpedo nuclease Dhp1(XRN2) to either deplete ordisplace RNAPII on chromatin in fission yeast metaphase cells, we show thatRNAPII does not load condensin on DNA. Instead, RNAPII retains condensin in cisand hinders its ability to fold mitotic chromatin and to support chromosomesegregation, consistent with the stalling of a loop extruder. Transcriptiontermination by Dhp1 limits such a hindrance. Our results shed light on theintegrated functioning of condensin, and we argue that a tight control oftranscription underlies mitotic chromosome assembly by loop-extruding condensin.
Assembly of a unique membrane complex in type VI secretion systems of Bacteroidota.: Author(s) : Bongiovanni T, Latario C, Le Cras Y, Trus E, Robitaille S, Swartz K, Schmidtke D, Vincent M, Kosta A, Orth J, Stengel F, Pellarin R, Rocha E, Ross B, Durand E,; Journal : Nat Commun; 2024; The type VI secretion system (T6SS) of Gram-negative bacteria inhibits competitorcells through contact-dependent translocation of toxic effector proteins. InProteobacteria, the T6SS is anchored to the cell envelope through amegadalton-sized membrane complex (MC). However, the genomes of Bacteroidota withT6SSs appear to lack genes encoding homologs of canonical MC components. Here, weidentify five genes in Bacteroides fragilis (tssNQOPR) that are essential forT6SS function and encode a Bacteroidota-specific MC. We purify this complex,reveal its dimensions using electron microscopy, and identify a protein-proteininteraction network underlying the assembly of the MC including the stoichiometryof the five TssNQOPR components. Protein TssN mediates the connection between theBacteroidota MC and the conserved baseplate. Although MC gene content andorganization varies across the phylum Bacteroidota, no MC homologs are detectedoutside of T6SS loci, suggesting ancient co-option and functional convergencewith the non-homologous MC of Pseudomonadota.

Sections

2024

The white gene as a transgenesis marker for the cricket Gryllus bimaculatus

Deciphering Molecular Mechanisms Involved in the Modulation of Human Aquaporins' Water Permeability by Zinc Cations: A Molecular Dynamics Approach.

Retinal atrophy, inflammation, phagocytic and metabolic disruptions develop in the MerTK-cleavage-resistant mouse model.

Structural insights into the N-terminal APHB domain of HrpA: mediating canonical and i-motif recognition.

The catalytic triad of rice NARROW LEAF1 involves H234.

Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite opposite effects in heart contraction.

Stimulation of ATP Hydrolysis by ssDNA Provides the Necessary Mechanochemical Energy for G4 Unfolding.

Aquaporin Modulation by Cations, a Review.

Plasticity and environment-specific relationships between gene expression and fitness in Saccharomyces cerevisiae.

Condensin loop extrusion properties, roadblocks, and role in homology search in S. cerevisiae

Space-Scale Hybrid Continuous-Discrete Sliding Frank-Wolfe Method

Transcription regulates the spatio-temporal dynamics of genes through micro-compartmentalization.

Mechanism of homology search expansion during recombinational DNA break repair in Saccharomyces cerevisiae.

A new type of non-Mendelian segregation.

Mechanism of homology search expansion during recombinational DNA break repair in Saccharomyces cerevisiae

The C. elegans SET1 histone methyltransferase SET-2 is not required for transgenerational memory of silencing.

AlphaFold2 Predicts Whether Proteins Interact Amidst Confounding Structural Compatibility

Dynamics of Protein–RNA Interfaces Using All-Atom Molecular Dynamics Simulations

Ultrastructure Expansion Microscopy applied to C. elegans embryos.

Translation-dependent and -independent mRNA decay occur through mutually exclusive pathways defined by ribosome density during T cell activation.

Stable structures or PABP1 loading protects cellular and viral RNAs against ISG20-mediated decay.

Metabolism-dependent secondary effect of anti-MAPK cancer therapy on DNA repair.

SIN-3 transcriptional coregulator maintains mitochondrial homeostasis and polyamine flux

Yeast cell responses and survival during periodic osmotic stress are controlled by glucose availability

RNAP II antagonizes mitotic chromatin folding and chromosome segregation by condensin.

Assembly of a unique membrane complex in type VI secretion systems of Bacteroidota.

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