Structural basis of ALC1/CHD1L autoinhibition and the mechanism of activation by the nucleosome

Li Wang,Kangjing Chen,Zhucheng Chen

doi:10.1038/s41467-021-24320-4

Li Wang, Kangjing Chen + Show 1 more

Open Access

https://doi.org/10.1038/s41467-021-24320-4

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Abstract

Chromatin remodeler ALC1 (amplification in liver cancer 1) is crucial for repairing damaged DNA. It is autoinhibited and activated by nucleosomal epitopes. However, the mechanisms by which ALC1 is regulated remain unclear. Here we report the crystal structure of human ALC1 and the cryoEM structure bound to the nucleosome. The structure shows the macro domain of ALC1 binds to lobe 2 of the ATPase motor, sequestering two elements for nucleosome recognition, explaining the autoinhibition mechanism of the enzyme. The H4 tail competes with the macro domain for lobe 2-binding, explaining the requirement for this nucleosomal epitope for ALC1 activation. A dual-arginine-anchor motif of ALC1 recognizes the acidic pocket of the nucleosome, which is critical for chromatin remodeling in vitro. Together, our findings illustrate the structures of ALC1 and shed light on its regulation mechanisms, paving the way for the discovery of drugs targeting ALC1 for the treatment of cancer.

Highlights

Chromatin remodeler ALC1 is crucial for repairing damaged DNA
Whereas hydrogen-deuterium exchange (HDX) and mutagenesis studies suggest that the macro domain interacts with lobe 2, small-angle x-ray scattering (SAXS), and crosslinking mass-spectrometry (XL-MS) suggest that ALC1 is in mixed conformations, with the macro domain binding either of the RecA-like domains[8,9]
ALC1 is notoriously flexible, and crystallization was achieved with single-chain antibodies, which were obtained by screening a yeast-display library

Summary

Introduction

Chromatin remodeler ALC1 (amplification in liver cancer 1) is crucial for repairing damaged DNA. It is autoinhibited and activated by nucleosomal epitopes. The structure shows the macro domain of ALC1 binds to lobe 2 of the ATPase motor, sequestering two elements for nucleosome recognition, explaining the autoinhibition mechanism of the enzyme. The H4 tail competes with the macro domain for lobe 2-binding, explaining the requirement for this nucleosomal epitope for ALC1 activation. The PAR chains bind to the macro domain of ALC1, releasing the autoinhibition of ALC1 and targeting the remodeler to the sites of DNA damage, where ALC1 slides the nucleosome and opens the chromatin[2,3,8]. The loss or inactivation of ALC1 in cells results in sensitivity to DNA damages[2]

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