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Mechanistic Insights into Autoinhibition of the Oncogenic Chromatin Remodeler ALC1

DOI: 10.1016/j.molcel.2017.10.017 DOI Help

Authors: Laura C. Lehmann (Uppsala University) , Graeme Hewitt (The Francis Crick Institute) , Shintaro Aibara (Stockholm University) , Alexander Leitner (Swiss Federal Institute of Technology) , Emil Marklund (Uppsala University) , Sarah L. Maslen (MRC Laboratory of Molecular Biology) , Varun Maturi (Uppsala University) , Yang Chen (Uppsala University) , David Van Der Spoel (Uppsala University) , J. Mark Skehel (MRC Laboratory of Molecular Biology) , Aristidis Moustakas (Uppsala University) , Simon J. Boulton (The Francis Crick Institute) , Sebastian Deindl (Uppsala University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecular Cell , VOL 68 , PAGES 847 - 859.e7

State: Published (Approved)
Published: December 2017
Diamond Proposal Number(s): 11171

Abstract: Human ALC1 is an oncogene-encoded chromatin-remodeling enzyme required for DNA repair that possesses a poly(ADP-ribose) (PAR)-binding macro domain. Its engagement with PARylated PARP1 activates ALC1 at sites of DNA damage, but the underlying mechanism remains unclear. Here, we establish a dual role for the macro domain in autoinhibition of ALC1 ATPase activity and coupling to nucleosome mobilization. In the absence of DNA damage, an inactive conformation of the ATPase is maintained by juxtaposition of the macro domain against predominantly the C-terminal ATPase lobe through conserved electrostatic interactions. Mutations within this interface displace the macro domain, constitutively activate the ALC1 ATPase independent of PARylated PARP1, and alter the dynamics of ALC1 recruitment at DNA damage sites. Upon DNA damage, binding of PARylated PARP1 by the macro domain induces a conformational change that relieves autoinhibitory interactions with the ATPase motor, which selectively activates ALC1 remodeling upon recruitment to sites of DNA damage.

Journal Keywords: ATP-dependent chromatin remodeler; chromatin remodeling; allosteric regulation; allostery; ATPase; structure; macro domain; PARP; ADP-ribosylation; DNA repair

Subject Areas: Biology and Bio-materials

Instruments: B21-High Throughput SAXS

Added On: 13/12/2017 10:41

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