2. Academic Validation
  3. A Poly-ADP-Ribose Trigger Releases the Auto-Inhibition of a Chromatin Remodeling Oncogene

A Poly-ADP-Ribose Trigger Releases the Auto-Inhibition of a Chromatin Remodeling Oncogene

  • Mol Cell. 2017 Dec 7;68(5):860-871.e7. doi: 10.1016/j.molcel.2017.11.019.
Hari R Singh 1,  Aurelio P Nardozza 1,  Ingvar R Möller 2,  Gunnar Knobloch 1,  Hans A V Kistemaker 3,  Markus Hassler 4,  Nadine Harrer 1,  Charlotte Blessing 1,  Sebastian Eustermann 5,  Christiane Kotthoff 1,  Sébastien Huet 6,  Felix Mueller-Planitz 1,  Dmitri V Filippov 3,  Gyula Timinszky 1,  Kasper D Rand 7,  Andreas G Ladurner 8
Affiliations

Affiliations

  • 1 Biomedical Center Munich, Faculty of Medicine, Ludwig-Maximilians-Universität München, Großhaderner Street 9, 82152 Planegg-Martinsried, Germany.
  • 2 Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
  • 3 Leiden Institute of Chemistry, Department of Bio-organic Synthesis, Leiden University, Einsteinweg 55, 2333 CC Leiden, the Netherlands.
  • 4 Biomedical Center Munich, Faculty of Medicine, Ludwig-Maximilians-Universität München, Großhaderner Street 9, 82152 Planegg-Martinsried, Germany; Cell Biology and Biophysics Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstraße 1, 69117 Heidelberg, Germany.
  • 5 Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen Street 25, 81377 Munich, Germany.
  • 6 CNRS, UMR 6290, Institut Génétique et Développement de Rennes, 35043 Rennes, France; Université de Rennes 1, Structure Fédérative de Recherche Biosit, 35043 Rennes, France.
  • 7 Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: [email protected].
  • 8 Biomedical Center Munich, Faculty of Medicine, Ludwig-Maximilians-Universität München, Großhaderner Street 9, 82152 Planegg-Martinsried, Germany; Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität München, Butenandt Street 13, 81377 Munich, Germany; Munich Cluster for Systems Neurology, Ludwig-Maximilians-Universität München, Feodor Lynen Street 17, 81377 Munich, Germany. Electronic address: [email protected].
PMID: 29220653 DOI: 10.1016/j.molcel.2017.11.019
Abstract

DNA damage triggers chromatin remodeling by mechanisms that are poorly understood. The oncogene and chromatin remodeler ALC1/CHD1L massively decompacts chromatin in vivo yet is inactive prior to DNA-damage-mediated PARP1 induction. We show that the interaction of the ALC1 macrodomain with the ATPase module mediates auto-inhibition. PARP1 activation suppresses this inhibitory interaction. Crucially, release from auto-inhibition requires a poly-ADP-ribose (PAR) binding macrodomain. We identify tri-ADP-ribose as a potent PAR-mimic and synthetic allosteric effector that abrogates ATPase-macrodomain interactions, promotes an ungated conformation, and activates the remodeler's ATPase. ALC1 fragments lacking the regulatory macrodomain relax chromatin in vivo without requiring PARP1 activation. Further, the ATPase restricts the macrodomain's interaction with PARP1 under non-DNA damage conditions. Somatic Cancer mutants disrupt ALC1's auto-inhibition and activate chromatin remodeling. Our data show that the NAD+-metabolite and nucleic acid PAR triggers ALC1 to drive chromatin relaxation. Modular allostery in this oncogene tightly controls its robust, DNA-damage-dependent activation.

Keywords

PARP; allostery; auto-inhibition; cancer; chromatin plasticity; enzyme; ligand; metabolite; oncogene; signaling.

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