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

TY - JOUR

T1 - A Poly-ADP-Ribose Trigger Releases the Auto-Inhibition of a Chromatin Remodeling Oncogene

AU - Singh, Hari R

AU - Nardozza, Aurelio P

AU - Möller, Ingvar R

AU - Knobloch, Gunnar

AU - Kistemaker, Hans A V

AU - Hassler, Markus

AU - Harrer, Nadine

AU - Blessing, Charlotte

AU - Eustermann, Sebastian

AU - Kotthoff, Christiane

AU - Huet, Sébastien

AU - Mueller-Planitz, Felix

AU - Filippov, Dmitri V

AU - Timinszky, Gyula

AU - Rand, Kasper D

AU - Ladurner, Andreas G

N1 - Copyright © 2017 Elsevier Inc. All rights reserved.

PY - 2017/12/7

Y1 - 2017/12/7

N2 - 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. 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.

AB - 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. 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.

KW - Journal Article

U2 - 10.1016/j.molcel.2017.11.019

DO - 10.1016/j.molcel.2017.11.019

M3 - Journal article

C2 - 29220653

SN - 1097-2765

VL - 68

SP - 860-871.e7

JO - Molecular Cell

JF - Molecular Cell

IS - 5

ER -