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

• Published in: Molecular cell 2017-12, Vol.68 (5), p.860-871.e7
• Main Authors: Singh, Hari R., Nardozza, Aurelio P., Möller, Ingvar R., Knobloch, Gunnar, Kistemaker, Hans A.V., Hassler, Markus, Harrer, Nadine, Blessing, Charlotte, Eustermann, Sebastian, Kotthoff, Christiane, Huet, Sébastien, Mueller-Planitz, Felix, Filippov, Dmitri V., Timinszky, Gyula, Rand, Kasper D., Ladurner, Andreas G.
• Format: Article
• Language: English
• Subjects: Allosteric Regulation; allostery; auto-inhibition; Binding Sites; Biochemistry, Molecular Biology; Cancer; Cell Line, Tumor; Chromatin Assembly and Disassembly; chromatin plasticity; DNA Damage; DNA Helicases - chemistry; DNA Helicases - genetics; DNA Helicases - metabolism; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; enzyme; Enzyme Activation; Genomics; Humans; Life Sciences; ligand; metabolite; Mutation; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - pathology; Nucleic Acid Conformation; oncogene; PARP; Poly (ADP-Ribose) Polymerase-1 - chemistry; Poly (ADP-Ribose) Polymerase-1 - genetics; Poly (ADP-Ribose) Polymerase-1 - metabolism; Poly Adenosine Diphosphate Ribose - chemistry; Poly Adenosine Diphosphate Ribose - metabolism; Poly ADP Ribosylation; Protein Binding; signaling; Structure-Activity Relationship; Time Factors
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2017.11.019

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. [Display omitted] •The ALC1 macrodomain mediates auto-inhibition of the remodeler’s ATPase activity•PARP1 hyper-activation suppresses the inhibitory protein-protein interaction•Tri-ADP-ribose promotes an ungated ALC1 conformation and triggers ATPase activity•Somatic cancer mutations disrupt ALC1’s auto-inhibitory mechanism in living cells The activity of the human oncogene and chromatin remodeler ALC1/CHD1L is strictly regulated by PARP1 activation. Singh et al. reveal how oligomers of ADP-ribose trigger the activation of ALC1 from an auto-inhibited state and identify cancer mutations that disrupt the NAD+-metabolite-regulated allosteric mechanism.