2. Academic Validation
  3. Mechanistic Insights into Regulation of the ALC1 Remodeler by the Nucleosome Acidic Patch

Mechanistic Insights into Regulation of the ALC1 Remodeler by the Nucleosome Acidic Patch

  • Cell Rep. 2020 Dec 22;33(12):108529. doi: 10.1016/j.celrep.2020.108529.
Laura C Lehmann 1,  Luka Bacic 1,  Graeme Hewitt 2,  Klaus Brackmann 1,  Anton Sabantsev 1,  Guillaume Gaullier 1,  Sofia Pytharopoulou 1,  Gianluca Degliesposti 3,  Hanneke Okkenhaug 4,  Song Tan 5,  Alessandro Costa 6,  J Mark Skehel 3,  Simon J Boulton 7,  Sebastian Deindl 8
Affiliations

Affiliations

  • 1 Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, 75124 Uppsala, Sweden.
  • 2 The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
  • 3 MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
  • 4 Imaging Facility, Babraham Institute, Cambridge CB22 3AT, UK.
  • 5 Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA.
  • 6 Macromolecular Machines Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
  • 7 The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address: [email protected].
  • 8 Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, 75124 Uppsala, Sweden. Electronic address: [email protected].
PMID: 33357431 DOI: 10.1016/j.celrep.2020.108529
Abstract

Upon DNA damage, the ALC1/CHD1L nucleosome remodeling Enzyme (remodeler) is activated by binding to poly(ADP-ribose). How activated ALC1 recognizes the nucleosome, as well as how this recognition is coupled to remodeling, is unknown. Here, we show that remodeling by ALC1 requires a wild-type acidic patch on the entry side of the nucleosome. The cryo-electron microscopy structure of a nucleosome-ALC1 linker complex reveals a regulatory linker segment that binds to the acidic patch. Mutations within this interface alter the dynamics of ALC1 recruitment to DNA damage and impede the ATPase and remodeling activities of ALC1. Full activation requires acidic patch-linker segment interactions that tether the remodeler to the nucleosome and couple ATP hydrolysis to nucleosome mobilization. Upon DNA damage, such a requirement may be used to modulate ALC1 activity via changes in the nucleosome acidic patches.

Keywords

ALC1; CHD1L; DNA damage; acidic patch; allosteric; chromatin; regulation; remodeler; remodeling; structure.

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