Recognition and remodelling of nucleosomes and hexasomes by the human INO80 complex

The ATP-dependent INO80 chromatin remodeller slides and repositions nucleosomes to shape and maintain chromatin around gene regulatory elements and replication origins. Recent work uncovered capabilities of yeast and fungal INO80 to bind and slide hexasomes, but whether this is a universal feature is unknown. Here, we show that also human INO80 slides hexasomes as efficiently as H2A and H2A.Z nucleosomes. By determining a variety of structures of human INO80 bound to canonical and H2A.Z nucleosomes as well as hexasomes, we reveal a predominantly topological sensing of nucleosomal species with at least three positions depending on entry DNA unwrapping. INO80 spin-rotates around the wheel like nucleosomal core particle, with the position determined by the Snf2 ATPase that binds the tangentially protruding entry DNA at various degrees of unwrapping. Acidic patch binding by IES2 can differentiate between different nucleosomal species, is important for nucleosome but not hexasome sliding, and can sense unwrapped exit DNA. These findings provide structural and mechanistic insights into how human INO80 remodels diverse chromatin substrates in a topology driven manner.