Cryo-EM Structure of ALC1 in an Open Conformation Bound to a PARylated Nucleosome.

Nucleosomes are the repeating unit of chromatin. They act as recognition platforms for chromatin-binding factors that coordinate genome maintenance. The chromatin remodeler Amplified in Liver Cancer 1 (ALC1) is a key component of the DNA-damage response and a promising therapeutic target in cancer. Through extensive classification of our previously deposited cryo-electron microscopy dataset, we identified a previously unresolved ALC1-nucleosome complex characterized by a more open conformation of ALC1. This is the first structure of ALC1 in which all domains are visualized in the context of a nucleosome complex, including the regulatory macro domain and a single α-helix motif within the linker. This newly identified conformation may represent an intermediate between the auto-inhibited and active states, and provides new structural insights into the conformational transitions that regulate the activity of ALC1.