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Mechanistic Insights into Autoinhibition of the Oncogenic Chromatin Remodeler ALC1.
Lehmann, Laura C; Hewitt, Graeme; Aibara, Shintaro; Leitner, Alexander; Marklund, Emil; Maslen, Sarah L; Maturi, Varun; Chen, Yang; van der Spoel, David; Skehel, J Mark; Moustakas, Aristidis; Boulton, Simon J; Deindl, Sebastian.
Afiliação
  • Lehmann LC; Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, 75124 Uppsala, Sweden.
  • Hewitt G; The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
  • Aibara S; Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, 17165 Solna, Sweden.
  • Leitner A; Department of Biology, Institute of Molecular Systems Biology, Swiss Federal Institute of Technology, 8093 Zürich, Switzerland.
  • Marklund E; Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, 75124 Uppsala, Sweden.
  • Maslen SL; MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
  • Maturi V; Department of Medical Biochemistry and Microbiology, and Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, 75123 Uppsala, Sweden.
  • Chen Y; Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, 75124 Uppsala, Sweden.
  • van der Spoel D; Department of Cell and Molecular Biology, Computational Biology and Bioinformatics, Uppsala University, 75124 Uppsala, Sweden.
  • Skehel JM; MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
  • Moustakas A; Department of Medical Biochemistry and Microbiology, and Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, 75123 Uppsala, Sweden.
  • Boulton SJ; The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address: simon.boulton@crick.ac.uk.
  • Deindl S; Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, 75124 Uppsala, Sweden. Electronic address: sebastian.deindl@icm.uu.se.
Mol Cell ; 68(5): 847-859.e7, 2017 Dec 07.
Article em En | MEDLINE | ID: mdl-29220652
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Dano ao DNA / Nucleossomos / DNA Helicases / Montagem e Desmontagem da Cromatina / Proteínas de Ligação a DNA / Reparo do DNA Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Mol Cell Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Suécia

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Dano ao DNA / Nucleossomos / DNA Helicases / Montagem e Desmontagem da Cromatina / Proteínas de Ligação a DNA / Reparo do DNA Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Mol Cell Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Suécia