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Mechanistic Insights into Autoinhibition of the Oncogenic Chromatin Remodeler ALC1
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
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Number of Authors: 132017 (English)In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 68, no 5, p. 847-859 (e7)Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2017. Vol. 68, no 5, p. 847-859 (e7)
Keywords [en]
ATP-dependent chromatin remodeler, chromatin remodeling, allosteric regulation, allostery, ATPase, structure, macro domain, PARP, ADP-ribosylation, DNA repair
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:su:diva-150983DOI: 10.1016/j.molcel.2017.10.017ISI: 000417646500006PubMedID: 29220652OAI: oai:DiVA.org:su-150983DiVA, id: diva2:1173377
Available from: 2018-01-12 Created: 2018-01-12 Last updated: 2018-01-12Bibliographically approved

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Hewitt, GraemeAibara, ShintaroMaturi, Varun
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