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  • Génomes

    • Vendredi 7 décembre 11:00-12:30 - Arjan de Groot - UMR 7265 CEA-CNRS-AMU, CEA Cadarache

      Radiation and oxidative stress resistance mechanisms in Deinococcus species : regulation and diversity

      Résumé : Deinococcus bacteria are extremely resistant to gamma radiation and other oxidative stress- and DNA damage-generating conditions. Among these bacteria, Deinococcus radiodurans has been studied most extensively, and the numerous data indicate that its extreme resistance results from a combination of multiple factors and well-regulated mechanisms that limit oxidative protein damage and enable repair of massive DNA damage.
      We are studying Deinococcus deserti using various approaches. One discovery was the exceptionally high proportion of leaderless mRNAs (i.e. lacking a 5’-untranslated region and Shine-Dalgarno sequence), including novel leaderless transcripts for small peptides (1). We also described a novel radiation response mechanism involving two proteins : a transcriptional repressor of DNA repair genes that is cleaved and inactivated be a specific, constitutively expressed metalloprotease (2). This SOS-independent response is crucial for radiation resistance. Recent data concerning the molecular mechanism by which radiation triggers repressor cleavage and gene induction will be presented (activation of the metalloprotease ; 3D structure of the repressor). The metalloprotease/repressor pair is highly conserved in different Deinococcus species. However, there is diversity in the set of genes regulated by these proteins (3). This observation stimulated us to search and compare more than 250 other radiation and oxidative stress resistance-associated proteins in the genomes of 11 radiation-resistant Deinococcus species. Strikingly, this revealed a large diversity of proteins involved in DNA repair (e.g. novel two-domain proteins) and oxidative stress defence, and in their regulation, even within the Deinococcus genus (4).
      (1) Genome Biol Evol 2014 ; 6:932–48. (2) Mol Microbiol 2014 ; 94:434–49. (3) MicrobiologyOpen 2017 ; 6:e477. (4) FEMS Microbiol Rev 2018/2019 ; doi : 10.1093/femsre/fuy037.

      Lieu : Salle Kalogeropoulos - Bât. 400, Campus d’Orsay

      Article

    • Vendredi 14 décembre 11:00-12:00 - Eleni Katsantoni - Basic Research Center, Biomedical Research Foundation, Academy of Athens, Athens, Greece

      Decoding the STAT5 activation and repression code

      Résumé : Signal transducer and activator of transcription 5 (STAT5) is a transcription factor that transduces signals from activated cell surface receptors to the nucleus to modulate transcription. STAT5 controls essential cellular functions and is encoded by two genes, Stat5a and Stat5b. STAT5 deficiency leads to severely impaired lymphoid development and perinatal death, and its constitutive activation is a hallmark of solid and hematologic malignancies. Thus, understanding its role in activation and repression of target genes is important for identification of biomarkers and designing novel molecular strategies for therapeutic management of such disorders. To understand the mechanisms of transcriptional activation and repression mediated by STAT5, we combined high-throughput genomics, transcriptomics and proteomics approaches. Using these approaches, the full genome-wide map of STAT5 target genes was generated and a network of interacting proteins was defined. Analysis of a STAT5a/LSD1/HDAC3 interactions network defined a dual function of LSD1 and HDAC3 on STAT5-dependent transcription (Nanou et al, 2016). Target genes of STAT5 and/or cofactors can be tested in the future for their potential use as biomarkers or therapeutic targets in various malignancies.
      Reference :
      Nanou A, Toumpeki C, Lavigne MD, Lazou V, Demmers J, Paparountas T, Thanos D, Katsantoni E. The dual role of LSD1 and HDAC3 in STAT5-dependent transcription is determined by protein interactions, binding affinities, motifs and genomic positions. Nucleic Acids Res. 2017 Jan 9 ;45(1):142-154
      Contact : Daan Noordermeer <daan.noordermeer i2bc.paris-saclay.fr>

      Lieu : Salle des séminaires- bâtiment 26 - Campus CNRS de Gif-sur-Yvette

      Article

  • I2BC

    • Vendredi 21 décembre 11:00-12:00 - Martine Simonelig - Institut de Génétique Humaine, Montpellier

      mRNA regulation by PIWI proteins and piRNAs in Drosophila

      Lieu : Auditorium I2BC - Bat 21, Campus de Gif-sur-Yvette

      Article

  • Microbiologie

    • Mardi 4 décembre 11:00-12:30 - Muriel Masi - « Membranes et Cibles Thérapeutiques », UMR_MD1, Inserm U1261 & IRBA, Aix-Marseille Université

      Envelope permeability, antibiotic accumulation and resistance in Gram-negative bacteria : New insights from the European IMI-TRANSLOCATION program

      Résumé : The alarming threat of multidrug resistant bacteria is leaving clinicians with very limited options to combat infections especially those caused by Gram-negative pathogens. As part of the European IMI antimicrobial resistance programme New Drugs for Bad Bugs, TRANSLOCATION aimed to increase the overall understanding of how Gram-negative bacteria accumulate antibiotics and come up with new solutions to fight against these pathogens (https://www.imi.europa.eu/content/translocation). During the last 5 years, my research projects focused on the bacterial cell envelope of clinically relevant Enterobacteriaceae as a permeability barrier that control antibiotic translocation, a key compartment that senses and responds to external antibiotic stresses, and a target for the development of new antimicrobials.
      In the first part of my talk, I will illustrate progress in WGS in linking bacterial genotypes and phenotypes, with the recent example of Enterobacter aerogenes. In this work, we report the evolution of antibiotic resistance of E. aerogenes strains that were sequentially isolated during the clinical course of two patients with imipenem. Comparative genomics of these isolates revealed a number of mutations, some of which located in genes encoding sensor kinases of regulatory two-component systems (TCS) — namely CpxA, PhoQ and PmrB. Cpx is an envelope stress response pathway that monitor and defend the bacterial cell envelope integrity against harmful conditions. It is constituted by the canonical CpxAR TCS and the periplasmic auxiliary protein CpxP. The CpxA mutation then was fully characterized in Escherichia coli K12 as a gain-of-function mutation that constitutively activates the Cpx stress response and confers a high level of resistance to various classes of antibiotics including β-lactams and aminoglycosides. This was mainly due to downregulation of outer membrane porins, upregulation of AmpC β-lactamase and AcrD efflux pump. In addition, the identified mutation that yielded to a Y144N substitution in the periplasmic sensing domain of the CpxA displaced interactions with CpxP in bacterial two-hybrid assay. Altogether our results clearly show the complex and intimate connection between β-lactam therapy, cell wall homeostasis and activation envelope stress response systems. This work also points to the major role of TCS in antibiotic-mediated stress adaptation and resistance, and validates TCS as new targets for antibiotic adjuvants.
      In the second part of my talk, I will discuss some of the conceptual and experimental challenges to understand rules for permeation through general porins and improve antibiotic accumulation. Reduced influx through outer membrane porins and increased efflux activity both mainly contribute to inadequate intracellular drug concentrations and times of residence close to their target. In this context, I will first present (micro)spectrofluorimetric approaches that allow quantification of the intracellular antibiotic content in intact cells. I will then present the recent development of a scoring function based on structural and physical properties of general porins and series of antibiotics β-lactam antibiotics. This scoring function correlated with in vitro permeation assays and in vivo antibacterial activity. Ultimately, we seek to use these approaches to identify physicochemical properties to improve the drug translocation, investigate the activity of permeability adjuvants, and screen for antibiotic accumulation defects in clinical strains.

      Lieu : Salle Kalogeropoulos - Bâtiment 400, Campus d’Orsay

      Article

  • cytoskeleton club

    • Mardi 11 décembre 11:30-13:00 - Alexis Gautreau - Ecole Polytechnique, CNRS UMR7654, Palaiseau

      Cytoskeleton club - Assembly of an actin polymerising machine : The WASH - Dynactin - Arp2/3 supercomplex

      Résumé : The Arp2/3 complex contains two Actin-related proteins (Arp), Arp2 and Arp3. At the surface of endosomes, the WASH complex activates the Arp2/3 complex and generates branched actin networks, which have been shown to be critical for endosomal sorting and recycling. The WASH complex is a stable multiprotein complex, which needs first to be assembled to perform its function. Here we report the identification of the first assembly factor of the WASH complex (Visweshwaran et al., EMBO J 2018). This assembly factor allows the assembly at centrosomes of a previously unrecognized trimeric WASH complex that carries most WASH functions. Up-regulation of the assembly factor enhances WASH complex assembly in invasive cancer cells and is associated with a poor survival prognosis of breast cancer patients. The WASH complex also recruits a pre-existing heterodimeric complex called the Capping Protein. We will present unpublished data showing that the WASH complex binds to and colocalizes with Dynactin. Dynactin is the major activator of the microtubule motor Dynein. Dynactin is a large multiprotein complex, which is organized along a capped minifilament containing Arp1 and 11. We were able to show that WASH appropriates CP from Dynactin and can thus elongate a primer filament that initiates the autocatalytic branched nucleation of actin filaments. These data thus ascribe a function to the Arp minifilament of Dynactin, show for the first time a role of Dynactin in polymerizing actin and illustrate how two Arp containing molecular machines perform endosomal membrane fission through the coordination of microtubule motors and actin polymerization.

      Lieu : Bibliothèque - bât. 34

      Article

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