Mechanistic Insights into Autoinhibition of the Oncogenic Chromatin Remodeler ALC1

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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. Lehmann et al. employ an integrative structural approach with biochemistry, cell-based assays, and in vivo imaging to investigate the regulation of ALC1. An unappreciated functional crosstalk between the PAR-binding macro domain and the ATPase underlies autoinhibition and activation of ALC1.

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Lehmann, L. C., Hewitt, G., Aibara, S., Leitner, A., Marklund, E., Maslen, S. L., … Deindl, S. (2017). Mechanistic Insights into Autoinhibition of the Oncogenic Chromatin Remodeler ALC1. Molecular Cell, 68(5), 847-859.e7. https://doi.org/10.1016/j.molcel.2017.10.017

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