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CONTRÔLE DE L’EXPRESSION DES GENES

Denise Aragnol Instabilité du génome et cancérogenèse CNRS/Université de la Méditerranée. CONTRÔLE DE L’EXPRESSION DES GENES. Chez les eucaryotes. DEFINITION D’EXPRESSION GENIQUE.

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CONTRÔLE DE L’EXPRESSION DES GENES

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  1. Denise Aragnol Instabilité du génome et cancérogenèse CNRS/Université de la Méditerranée CONTRÔLE DE L’EXPRESSION DES GENES Chez les eucaryotes

  2. DEFINITION D’EXPRESSION GENIQUE Expression génique : recouvre l’ensemble des mécanismes qui conduisent à l’apparition d’un produit fonctionnel d’un gène Produit fonctionnel: -Une protéine transcription + traduction -Un ARN  transcription

  3. LES DIFFERENTS TYPES D’ARN traduction

  4. TOUTES LES ETAPES DE L’EXPRESSION GENIQUE SONT REGULEES nucleus RNA localisation cytoplasm a more accurate outline of the events involved in genome expression, especially in higher organisms. Note that these schemes apply only to protein-coding genes. Those genes that give rise to non-coding RNAs are transcribed and processed as shown but the RNAs are not translated. Protein localisation

  5. UN EXEMPLE D’ARNm LOCALISE Movement of RNA-containing granules in dendrites of cultured neurons.a–k | Time-lapse images, taken 20 s apart, of an anterograde-moving granule (arrow). The granule is detected by visualization of fluorescent SYTO-14, which binds to RNA. The granule moves more than 5 m, with an average velocity of 0.04 m s-1. This movement was stimulated by depolarization

  6. IMPORTANCE DES INTERACTIONS MOLECULAIRES

  7. nucleus TOUTES LES ETAPES DE L’EXPRESSION GENIQUE SONT REGULEES RNA localisation cytoplasm Protein localisation

  8. UN SYNOPSIS DE LA TRANSCRIPTION

  9. LES PROMOTEURS EUCARYOTES SONT COMPLEXES EXEMPLE DE PROMOTEUR RECONNU PAR L’ARN POL II -TATAbox (-25) TATAWAW avec W=A ou T -Inr YYA(+1)NWYY avec Y=C ou T

  10. L’ORGANISATION DES PROMOTEURS EUCARYOTE EST DIFFERENTE D’UN GENE A UN AUTRE Eukaryotic promoters consist of a collection of conserved short sequence elements located at relatively diverse distances from the transcription start site. Alternative orientations for GC and CAAT box elements are indicated by chevron orientation: > = normal orientation; < = reverse orientation. The glucocorticoid receptor gene is unusual in possessing 13 upstream GC boxes (10 in the normal orientation; three in the reverse orientation).

  11. LES ARN POLYMERASES EUCARYOTES -3 ARNpol différentes: ARN pol I, ARN Pol II, ARN Pol III compositions et fonctions différentes, structures similaires -multimériques (8 à 12 s. u.); >500kDa; L’ARNpol II eucaryote est constituée de plus de 10 sous-unités Functions of the three eukaryotic nuclear RNA polymerases Polymerase Genes transcribed ____________________________________________________ RNA polymerase I (nucléole) 28S, 5.8S and 18S ribosomal RNA (rRNA) genes RNA polymerase II Protein-coding genes; most small nuclear RNA (snRNA) genes RNA polymerase III Genes for transfer RNAs (tRNA), 5S rRNA, U6-snRNA, small nucleolar (sno) RNAs, small cytoplasmic (sc) RNA

  12. STRUCTURE DE L’ARN pol II (2001) B.Enzyme en élongation à une résolution de 3,3 Å.La pince formée de parties de Rbp1 et Rbp2 effectue une rotation de 30 ° qui maintient la matrice d ’ADN et le transcrit au sein du complexe transcriptionnel. L ’extrapolation du trajet probable des acides nucléiques au sein de l ’enzyme montre que l ’ADN double brin situé en aval fait contact avec la mâchoire inférieure puis passe entre le lobe de Rbp2 et une partie de la pince formée par Rbp1.Des flèches indiquent les sites d ’entrée et de sortie de l ’ADN (Protein Data Bank Accession Code :1i6H). Violet :mâchoire supérieure;rose :mâchoire inférieure;jaune :lobe;vert foncé :sillon;blanc :hélice de pontage;orange :site actif;vert pâle : pore;bleu :mur;rouge :pince;bleu pâle :ions Mg 2+(Protein Data Bank Accession Code :1i50).Bleu :brin matrice;vert :brin codant;rose :ARN. Le code de couleur des domaines de l ’enzyme est le même qu ’en (A) Structure cristallographique de l ’ARN polymérase II. A. Enzyme libre à une résolution de 2,8 Å.L ’enzyme contient un sillon (Rpb1)bordé à son entrée par une paire de mâchoires, supérieure (partie de Rpb1 et Rpb9) et inférieure (Rbp5), et au fond duquel se trouvent deux ions Mg 2+ qui indiquent l ’emplacement du site actif. Près du site actif, l’hélice de pontage (Rpb1) traverse le sillon pour rejoindre Rpb2. Le pore localisé à l ’arrière de l ’enzyme permettrait l’entrée des rNTP et la sortie de l ’extrémité 3 ’ libre (Protein Data Bank Accession Code :1i50).

  13. LES CARACTERISTIQUES DU DOMAINE C-TER de l’ARN pol II La RNA pol II possède un domaine C terminal particulier, constitué de répétitions d’un heptapeptide (tyr-ser-pro-thr-ser-pro-ser) qui peut présenter différents niveaux de phosphorylation

  14. LES FACTEURS GENERAUX PIC: préinitiation complex

  15. LES FACTEURS EN AMONT

  16. DEBUT DE L’ELONGATION 5’ 3’ CAAT TATA ATAT TAAC 3’ 5’ 5’ 5’ 3’ CAAT TATA ATAT TAAC 3’ 5’ 5’

  17. ELONGATION ET MATURATION SONT COUPLEES

  18. ADDITION DE LA COIFFE The C-Terminal Domain (CTD) of RNA Polymerase II Coordinates Transcription and Pre-mRNA ProcessingThe CTD consists of 52 repeats of the consensus heptapeptide Tyr-Ser-Pro-Thr-Ser-Pro-Ser and serves as a platform for the ordered assembly of the factors responsible for transcription, pre-mRNA 5′ capping, splicing, and 3′ processing at different stages in the synthesis of the nascent transcript.

  19. L’EXCISION EPISSAGE DES INTRONS Structure of U1-snRNP. The mammalian U1-snRNP comprises the 165-nucleotide U1-RNA plus ten proteins. Three of these (U1-70K, U1-A and U1-C) are specific to this snRNP, the other seven are Sm proteins that are found in all the snRNPs involved in splicing. The U1-RNA forms a base-paired structure as shown. The U1-70K and U1-A proteins attach to two of the major stem-loops of this base-paired structure, and U1-C attaches via a protein-protein interaction. The Sm proteins attach to the Sm site. Based on Stark et al. (2001)

  20. FORMATION DE L’EXTREMITE 3’ DE L’ARNm CPSF: Cleavage &polyadenylation specificity factor CstF: cleavage stimulation factor PAP: polyA polymerase

  21. DE NOUVELLES INTERACTIONS AU NIVEAU DU CTD DE L’ARN pol II Schematic representation of the polyadenylation machinery. The majority of the components of the mammalian and yeast polyadenylation complexes are conserved, including all currently known factors that function in the transcription connection. For simplicity, only the mammalian nomenclature is depicted; the yeast names of factors that have important roles in the events described here are also indicated. (Note that although an apparent human homolog of Ssu72 exists, it has not yet been characterized functionally). , documented protein–protein interactions that help link transcription and 3' processing (see text). Polyadenylation signal sequences (upstream AAUAAA, CA cleavage site consensus, and downstream G/U-rich region) are boxed. CPSF, cleavage-polyadenylation specificity factor; CstF, cleavage stimulation factor; CFI and CFII, cleavage factors I and II, respectively; PAP, poly(A) polymerase.

  22. LA TRANSCRIPTION EST REGULEE cytoplasme noyau cytoplasme noyau

  23. DES FACTEURS DE TRANSCRIPTION SPECIFIQUES INTERAGISSENT AVEC LA MACHINERIE BASALE DE TRANSCRIPTION

  24. ACTIVATION TRANSCRIPTIONNELLE PAR UNE HORMONE

  25. CHROMATINE ET TRANSCRIPTION

  26. LA CHROMATINE C’est la structure macromoléculaire ADN-protéine présente dans le noyau des cellules eucaryotes Le nucléosome 147 pb d’ADN sont enroulés autour de l’octamere d’histone, formant deux tours

  27. LA CHROMATINE CONSTITUE UN CONTEXTE TRANSCRIPTIONNEL REPRESSIF

  28. LE CODE HISTONE Histone Modifications on the Nucleosome Core ParticleThe nucleosome core particle showing 6 of the 8 core histone N-terminal tail domains and 2 C-terminal tails. Sites of posttranslational modification are indicated by colored symbols that are defined in the key (lower left); acK, acetyl lysine; meR, methyl arginine; meK, methyl lysine; PS, phosphoryl serine; and uK, ubiquitinated lysine. Residue numbers are shown for each modification. Note that H3 lysine 9 can be either acetylated or methylated. The C-terminal tail domains of one H2A molecule and one H2B molecule are shown (dashed lines) with sites of ubiquitination at H2A lysine 119 (most common in mammals) and H2B lysine 123 (most common in yeast). Modifications are shown on only one of the two copies of histones H3 and H4 and only one tail is shown for H2A and H2B. Sites marked by green arrows are susceptible to cutting by trypsin in intact nucleosomes. Note that the cartoon is a compendium of data from various organisms, some of which may lack particular modifications (e.g., there is no H3meK9 in S. cerevisiae). Adapted from Spotswood and Turner (2002 ).

  29. L’EPIGENETIQUE

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