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21 juillet 2017: 1 événement

  • Département Biologie des Génomes

    Vendredi 21 juillet 2017 11:00-12:00 - Dr Cedric R. Clapier - Huntsman Cancer Institute and Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, USA

    Regulatory architecture and logic of chromatin remodelers

    Résumé : Chromatin remodelers contain an ATPase that operates as a DNA-translocating motor, which propels DNA around the histone octamer, leading to nucleosome sliding, ejection, or histone variant installation and removal. How various remodelers function and their ATPase-translocase regulated are the subject of intense investigations.
    We demonstrated (Clapier & Cairns, Nature, 2012) that ISWI, the motor of ISWI-subfamily remodelers involved in chromatin assembly, contains an intrinsically active DNA translocase able to perform nucleosome sliding. This by default active core is repressed by two newly-discovered flanking regions, AutoN inhibiting ATPase activity, and NegC inhibiting ‘coupling’, the amount of DNA translocated relative to ATP hydrolysis. Regulated activation of the motor is achieved by selective ‘inhibition of inhibition’ with two nucleosomal epitopes, the H4 basic patch and the linker DNA, relieving the AutoN and NegC brakes respectively. Notably, this study ruled out the alternative ‘power stroke’ model.
    We also investigated (Clapier et al., Mol. Cell, 2016) whether and how DNA translocation is regulated to achieve nucleosome sliding versus ejection by studying Sth1, the motor of RSC, a SWI/SNF-subfamily remodeler involved in chromatin access. We reported the regulation of DNA translocation efficiency by the Post-HSA and Protrusion 1 domains and by actin-related proteins (ARPs), residing within or binding to Sth1. By improving coupling, ARPs facilitate sliding and are needed for ejection by RSC. Mutations identified in Protrusion 1 and Post-HSA promote coupling and improve ATP hydrolysis respectively ; and the strongest mutations conferred efficient nucleosome ejection without ARPs in vitro and altered nucleosomal positioning in vivo. Thus, sliding-to-ejection involves a continuum of DNA translocation efficiency.
    These studies, along with work by many others, prompt a reconsideration of remodeler diversity. We propose an ‘hourglass’ model for chromatin remodeling (Clapier & Cairns, Nat. Rev. Mol. Cell Biol., 2017) ; remodelers have diverse compositions, but converge to share the unifying property of DNA translocation carried out within the nucleosome, followed by divergence via specialized regulatory proteins and domains, that help inform the ATPase whether and how to apply DNA translocation, determining remodeling outcomes.
    Invité par Michel Werner, équipe Régulation transcriptionnelle des génomes

    Lieu : Auditorium - bâtiment21, campus de gif

    En savoir plus : Département Biologie des Génomes