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Mechanistic Insights into Autoinhibition of the Oncogenic Chromatin Remodeler ALC1
Laura C Lehmann1, Graeme Hewitt2, Shintaro Aibara3
1Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, 75124 Uppsala, Sweden.
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.
Insights
Human ALC1, a DNA repair enzyme, is regulated by its PAR-binding macro domain. This domain controls ALC1
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Human ALC1 (Amplified in Liver Cancer 1) is a chromatin-remodeling enzyme crucial for DNA repair pathways.
- ALC1 possesses a poly(ADP-ribose) (PAR)-binding macro domain, which interacts with PARylated PARP1 (Poly(ADP-ribose) Polymerase 1).
- The precise mechanism by which PARylated PARP1 binding activates ALC1 at DNA damage sites is not fully understood.
Purpose of the Study:
- To elucidate the dual role of the ALC1 macro domain in regulating ATPase activity and nucleosome mobilization.
- To investigate the mechanism of ALC1 autoinhibition and activation by PARylated PARP1.
- To determine the structural and functional consequences of mutations affecting the macro domain-PARP1 interaction.
Main Methods:
- Biochemical assays to measure ALC1 ATPase activity.
- Site-directed mutagenesis to disrupt specific interactions within ALC1.
- Analysis of ALC1 recruitment dynamics at DNA damage sites using live-cell imaging.
- Structural analysis to understand conformational changes.
Main Results:
- The ALC1 macro domain acts as an autoinhibitory domain, maintaining the enzyme in an inactive state through electrostatic interactions with the ATPase lobe in the absence of DNA damage.
- Mutations disrupting the macro domain-ATPase interface lead to constitutive ALC1 ATPase activity, independent of PARylated PARP1.
- PARylated PARP1 binding to the macro domain induces a conformational change, relieving autoinhibition and selectively activating ALC1's chromatin remodeling function at DNA damage sites.
Conclusions:
- The ALC1 macro domain plays a critical dual role in both autoinhibition of ATPase activity and coupling to nucleosome mobilization.
- Conformational changes mediated by PARylated PARP1 binding are essential for ALC1 activation and recruitment to DNA damage sites.
- Understanding ALC1 regulation provides insights into DNA repair mechanisms and potential therapeutic strategies targeting oncogenes.
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