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Accueil > Départements > Biologie des Génomes > Daniel GAUTHERET : Séquence, Structure et Fonction des ARN

Séquence, Structure et Fonction des ARN

Publications de l’équipe


  • J. Lehmann, « Induced fit of the peptidyl-transferase center of the ribosome and conformational freedom of the esterified amino acids », RNA (New York, N.Y.), vol. 23, nᵒ 2, p. 229-239, 2017.
    Résumé : The catalytic site of most enzymes can efficiently handle only one substrate. In contrast, the ribosome is capable of polymerizing at a similar rate at least 20 different kinds of amino acids from aminoacyl-tRNA carriers while using just one catalytic site, the peptidyl-transferase center (PTC). An induced-fit mechanism has been uncovered in the PTC, but a possible connection between this mechanism and the uniform handling of the substrates has not been investigated. We present an analysis of published ribosome structures supporting the hypothesis that the induced fit eliminates unreactive rotamers predominantly populated for some A-site aminoacyl esters before induction. We show that this hypothesis is fully consistent with the wealth of kinetic data obtained with these substrates. Our analysis reveals that induction constrains the amino acids into a reactive conformation in a side-chain independent manner. It allows us to highlight the rationale of the PTC structural organization, which confers to the ribosome the very unusual ability to handle large as well as small substrates.
    Mots-clés : aminoacyl-tRNA, DBG, EF-P, induced fit, peptidyl-transferase center, Ribosome, SSFA.


  • F. Leclerc, G. Zaccai, J. Vergne, M. Řìhovà, A. Martel, et M. - C. Maurel, « Self-assembly Controls Self-cleavage of HHR from ASBVd (-): a Combined SANS and Modeling Study », Scientific Reports, vol. 6, p. 30287, 2016.
    Résumé : In the Avocado Sunblotch Viroid (ASBVd: 249-nt) from the Avsunviroidae family, a symmetric rolling-circle replication operates through an autocatalytic mechanism mediated by hammerhead ribozymes (HHR) embedded in both polarity strands. The concatenated multimeric ASBVd (+) and ASBVd (-) RNAs thus generated are processed by cleavage to unit-length where ASBVd (-) self-cleaves with more efficiency. Absolute scale small angle neutron scattering (SANS) revealed a temperature-dependent dimer association in both ASBVd (-) and its derived 79-nt HHR (-). A joint thermodynamic analysis of SANS and catalytic data indicates the rate-determining step corresponds to the dimer/monomer transition. 2D and 3D models of monomeric and dimeric HHR (-) suggest that the inter-molecular contacts stabilizing the dimer (between HI and HII domains) compete with the intra-molecular ones stabilizing the active conformation of the full-length HHR required for an efficient self-cleavage. Similar competing intra- and inter-molecular contacts are proposed in ASBVd (-) though with a remoter region from an extension of the HI domain.
    Mots-clés : DBG, SSFA.

  • J. Lehmann, A. Libchaber, et B. D. Greenbaum, « Fundamental amino acid mass distributions and entropy costs in proteomes », Journal of Theoretical Biology, vol. 410, p. 119-124, 2016.
    Résumé : We examine whether the frequency of amino acids across an organism's proteome is primarily determined by optimization to function or other factors, such as the structure of the genetic code. Considering all available proteins together, we first point out that the frequency of an amino acid in a proteome negatively correlates with its mass, suggesting that the genome preserves a fundamental distribution ruled by simple energetics. Given the universality of such distributions, one can use outliers, cysteine and leucine, to identify amino acids that deviate from this simple rule for functional purposes and examine those functions. We quantify the strength of such selection as the entropic cost outliers pay to defy the mass-frequency relation. Codon degeneracy of an amino acid partially explains the correlation between mass and frequency: light amino acids being typically encoded by highly degenerate codon families, with the exception of arginine. While degeneracy may be a factor in hard wiring the relationship between mass and frequency in proteomes, it does not provide a complete explanation. By examining extremophiles, we are able to show that this law weakens with temperature, likely due to protein stability considerations, thus the environment is essential.
    Mots-clés : Amino acid statistics, DBG, Extremophiles, Genetic code origin, Genome evolution, SSFA.

  • M. - C. Maurel et F. Leclerc, « From Foundation Stones to Life: Concepts and Results », Elements, vol. 12, nᵒ 6, p. 407-412, 2016.

  • V. D. T. Tran, O. Souiai, N. Romero-Barrios, M. Crespi, et D. Gautheret, « Detection of generic differential RNA processing events from RNA-seq data », RNA Biology, vol. 13, nᵒ 1, p. 59-67, janv. 2016.
    Mots-clés : DBG, eBio, PF, SSFA.

  • M. Wery, M. Descrimes, N. Vogt, A. - S. Dallongeville, D. Gautheret, et A. Morillon, « Nonsense-Mediated Decay Restricts LncRNA Levels in Yeast Unless Blocked by Double-Stranded RNA Structure », Molecular Cell, vol. 61, nᵒ 3, p. 379-392, 2016.
    Mots-clés : DBG, eBio, PF, SSFA.


  • M. Cossu, V. Da Cunha, C. Toffano-Nioche, P. Forterre, et J. Oberto, « Comparative genomics reveals conserved positioning of essential genomic clusters in highly rearranged Thermococcales chromosomes », Biochimie, vol. 118, p. 313-321, 2015.
    Résumé : The genomes of the 21 completely sequenced Thermococcales display a characteristic high level of rearrangements. As a result, the prediction of their origin and termination of replication on the sole basis of chromosomal DNA composition or skew is inoperative. Using a different approach based on biologically relevant sequences, we were able to determine oriC position in all 21 genomes. The position of dif, the site where chromosome dimers are resolved before DNA segregation could be predicted in 19 genomes. Computation of the core genome uncovered a number of essential gene clusters with a remarkably stable chromosomal position across species, in sharp contrast with the scrambled nature of their genomes. The active chromosomal reorganization of numerous genes acquired by horizontal transfer, mainly from mobile elements, could explain this phenomenon.
    Mots-clés : Archaea, ARCHEE, Base Sequence, Bioinformatics, Chromosomal landmarks, Chromosomes, Comparative Genomic Hybridization, DBG, Evolution, Molecular, Gene Rearrangement, Genes, Archaeal, Genome, Genome evolution, MICROBIO, Mobile elements, Molecular Sequence Data, SSFA, Thermococcales.

  • J. Li, D. Drubay, S. Michiels, et D. Gautheret, « Mining the coding and non-coding genome for cancer drivers », Cancer Letters, vol. 369, nᵒ 2, p. 307-315, 2015.
    Résumé : Progress in next-generation sequencing provides unprecedented opportunities to fully characterize the spectrum of somatic mutations of cancer genomes. Given the large number of somatic mutations identified by such technologies, the prioritization of cancer-driving events is a consistent bottleneck. Most bioinformatics tools concentrate on driver mutations in the coding fraction of the genome, those causing changes in protein products. As more non-coding pathogenic variants are identified and characterized, the development of computational approaches to effectively prioritize cancer-driving variants within the non-coding fraction of human genome is becoming critical. After a short summary of methods for coding variant prioritization, we here review the highly diverse non-coding elements that may act as cancer drivers and describe recent methods that attempt to evaluate the deleteriousness of sequence variation in these elements. With such tools, the prioritization and identification of cancer-implicated regulatory elements and non-coding RNAs is becoming a reality.
    Mots-clés : Bioinformatics, Cancer drivers, Computational Biology, DBG, Genome, Human, Humans, Mutation, Neoplasms, Non-coding drivers, Somatic mutation scoring, SSFA.

  • J. Li, M. - A. Poursat, D. Drubay, A. Motz, Z. Saci, A. Morillon, S. Michiels, et D. Gautheret, « A Dual Model for Prioritizing Cancer Mutations in the Non-coding Genome Based on Germline and Somatic Events », PLoS computational biology, vol. 11, nᵒ 11, p. e1004583, 2015.
    Résumé : We address here the issue of prioritizing non-coding mutations in the tumoral genome. To this aim, we created two independent computational models. The first (germline) model estimates purifying selection based on population SNP data. The second (somatic) model estimates tumor mutation density based on whole genome tumor sequencing. We show that each model reflects a different set of constraints acting either on the normal or tumor genome, and we identify the specific genome features that most contribute to these constraints. Importantly, we show that the somatic mutation model carries independent functional information that can be used to narrow down the non-coding regions that may be relevant to cancer progression. On this basis, we identify positions in non-coding RNAs and the non-coding parts of mRNAs that are both under purifying selection in the germline and protected from mutation in tumors, thus introducing a new strategy for future detection of cancer driver elements in the expressed non-coding genome.
    Mots-clés : Computational Biology, DBG, eBio, Genome, Human, Humans, Models, Genetic, Mutation, Neoplasms, PF, RNA, Untranslated, Sequence Analysis, DNA, SSFA.

  • A. E. Martínez de Alba, A. B. Moreno, M. Gabriel, A. C. Mallory, A. Christ, R. Bounon, S. Balzergue, S. Aubourg, D. Gautheret, M. D. Crespi, H. Vaucheret, et A. Maizel, « In plants, decapping prevents RDR6-dependent production of small interfering RNAs from endogenous mRNAs », Nucleic Acids Research, vol. 43, nᵒ 5, p. 2902-2913, 2015.
    Résumé : Cytoplasmic degradation of endogenous RNAs is an integral part of RNA quality control (RQC) and often relies on the removal of the 5' cap structure and their subsequent 5' to 3' degradation in cytoplasmic processing (P-)bodies. In parallel, many eukaryotes degrade exogenous and selected endogenous RNAs through post-transcriptional gene silencing (PTGS). In plants, PTGS depends on small interfering (si)RNAs produced after the conversion of single-stranded RNAs to double-stranded RNAs by the cellular RNA-dependent RNA polymerase 6 (RDR6) in cytoplasmic siRNA-bodies. PTGS and RQC compete for transgene-derived RNAs, but it is unknown whether this competition also occurs for endogenous transcripts. We show that the lethality of decapping mutants is suppressed by impairing RDR6 activity. We establish that upon decapping impairment hundreds of endogenous mRNAs give rise to a new class of rqc-siRNAs, that over-accumulate when RQC processes are impaired, a subset of which depending on RDR6 for their production. We observe that P- and siRNA-bodies often are dynamically juxtaposed, potentially allowing for cross-talk of the two machineries. Our results suggest that the decapping of endogenous RNA limits their entry into the PTGS pathway. We anticipate that the rqc-siRNAs identified in decapping mutants represent a subset of a larger ensemble of endogenous siRNAs.
    Mots-clés : Arabidopsis, Arabidopsis Proteins, DBG, Endoribonucleases, Gene Expression Regulation, Plant, Mutation, Oligonucleotide Array Sequence Analysis, Plants, Genetically Modified, RNA Caps, RNA Interference, RNA Replicase, RNA, Messenger, RNA, Plant, RNA, Small Interfering, RNA, Small Untranslated, SSFA, Transcriptome.

  • A. Pain, A. Ott, H. Amine, T. Rochat, P. Bouloc, et D. Gautheret, « An assessment of bacterial small RNA target prediction programs », RNA biology, vol. 12, nᵒ 5, p. 509-513, 2015.
    Résumé : Most bacterial regulatory RNAs exert their function through base-pairing with target RNAs. Computational prediction of targets is a busy research field that offers biologists a variety of web sites and software. However, it is difficult for a non-expert to evaluate how reliable those programs are. Here, we provide a simple benchmark for bacterial sRNA target prediction based on trusted E. coli sRNA/target pairs. We use this benchmark to assess the most recent RNA target predictors as well as earlier programs for RNA-RNA hybrid prediction. Moreover, we consider how the definition of mRNA boundaries can impact overall predictions. Recent algorithms that exploit both conservation of targets and accessibility information offer improved accuracy over previous software. However, even with the best predictors, the number of true biological targets with low scores and non-targets with high scores remains puzzling.
    Mots-clés : bacteria, Base Pairing, Computational Biology, DBG, Escherichia coli, RNA, Bacterial, RNA, Messenger, sRNA, sRNA target prediction, SRRB, SSFA, Untranslated Regions.

  • Y. Ponty et F. Leclerc, « Drawing and editing the secondary structure(s) of RNA », Methods in Molecular Biology (Clifton, N.J.), vol. 1269, p. 63-100, 2015.
    Résumé : Secondary structure diagrams are essential, in RNA biology, to communicate functional hypotheses and summarize structural data, and communicate them visually as drafts or finalized publication-ready figures. While many tools are currently available to automate the production of such diagrams, their capacities are usually partial, making it hard for a user to decide which to use in a given context. In this chapter, we guide the reader through the steps involved in the production of expressive publication-quality illustrations featuring the RNA secondary structure. We present major existing representations and layouts, and give precise instructions to produce them using available free software, including jViz.RNA, the PseudoViewer, RILogo, R-chie, RNAplot, R2R, and VARNA. We describe the file formats and structural descriptions accepted by popular RNA visualization tools. We also provide command lines and Python scripts to ease the user's access to advanced features. Finally, we discuss and illustrate alternative approaches to visualize the secondary structure in the presence of probing data, pseudoknots, RNA-RNA interactions, and comparative data.
    Mots-clés : Algorithms, Computational Biology, Computer Graphics, DBG, Nucleic Acid Conformation, RNA, Software, SSFA, User-Computer Interface.

  • F. Rambow, B. Job, V. Petit, F. Gesbert, V. Delmas, H. Seberg, G. Meurice, E. Van Otterloo, P. Dessen, C. Robert, D. Gautheret, R. A. Cornell, A. Sarasin, et L. Larue, « New Functional Signatures for Understanding Melanoma Biology from Tumor Cell Lineage-Specific Analysis », Cell Reports, vol. 13, nᵒ 4, p. 840-853, 2015.
    Résumé : Molecular signatures specific to particular tumor types are required to design treatments for resistant tumors. However, it remains unclear whether tumors and corresponding cell lines used for drug development share such signatures. We developed similarity core analysis (SCA), a universal and unsupervised computational framework for extracting core molecular features common to tumors and cell lines. We applied SCA to mRNA/miRNA expression data from various sources, comparing melanoma cell lines and metastases. The signature obtained was associated with phenotypic characteristics in vitro, and the core genes CAPN3 and TRIM63 were implicated in melanoma cell migration/invasion. About 90% of the melanoma signature genes belong to an intrinsic network of transcription factors governing neural development (TFAP2A, DLX2, ALX1, MITF, PAX3, SOX10, LEF1, and GAS7) and miRNAs (211-5p, 221-3p, and 10a-5p). The SCA signature effectively discriminated between two subpopulations of melanoma patients differing in overall survival, and classified MEKi/BRAFi-resistant and -sensitive melanoma cell lines.
    Mots-clés : breast, Cell Lineage, colon, Computational Biology, DBG, Ewing sarcoma, glioblastoma, Humans, liver, lung, Melanoma, MicroRNAs, miRNA, neuroblastoma, ovary, phenotype switching, SSFA, survival, Transcriptome.

  • C. Toffano-Nioche, D. Gautheret, et F. Leclerc, « Revisiting the structure/function relationships of H/ACA(-like) RNAs: a unified model for Euryarchaea and Crenarchaea », Nucleic Acids Research, vol. 43, nᵒ 16, p. 7744-7761, 2015.
    Résumé : A structural and functional classification of H/ACA and H/ACA-like motifs is obtained from the analysis of the H/ACA guide RNAs which have been identified previously in the genomes of Euryarchaea (Pyrococcus) and Crenarchaea (Pyrobaculum). A unified structure/function model is proposed based on the common structural determinants shared by H/ACA and H/ACA-like motifs in both Euryarchaea and Crenarchaea. Using a computational approach, structural and energetic rules for the guide:target RNA-RNA interactions are derived from structural and functional data on the H/ACA RNP particles. H/ACA(-like) motifs found in Pyrococcus are evaluated through the classification and their biological relevance is discussed. Extra-ribosomal targets found in both Pyrococcus and Pyrobaculum might support the hypothesis of a gene regulation mediated by H/ACA(-like) guide RNAs in archaea.
    Mots-clés : Base Pairing, DBG, Euryarchaeota, Gene Expression Regulation, Archaeal, Models, Molecular, Nucleotide Motifs, Pyrobaculum, Pyrococcus abyssi, RNA Folding, RNA, Archaeal, RNA, Guide, RNA, Small Nucleolar, RNA, Transfer, SSFA, Structure-Activity Relationship.
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