Abstract
ISWI family chromatin remodeling motors use sophisticated autoinhibition mechanisms to control nucleosome sliding. Yet how the different autoinhibitory domains are regulated is not well understood. Here we show that an acidic patch formed by histones H2A and H2B of the nucleosome relieves the autoinhibition imposed by the AutoN and the NegC regions of the human ISWI remodeler SNF2h. Further, by single molecule FRET we show that the acidic patch helps control the distance travelled per translocation event. We propose a model in which the acidic patch activates SNF2h by providing a landing pad for the NegC and AutoN auto-inhibitory domains. Interestingly, the INO80 complex is also strongly dependent on the acidic patch for nucleosome sliding, indicating that this substrate feature can regulate remodeling enzymes with substantially different mechanisms. We therefore hypothesize that regulating access to the acidic patch of the nucleosome plays a key role in coordinating the activities of different remodelers in the cell.
Highlights
Eukaryotic genomes are packaged into chromatin, enabling large amounts of DNA to fit into the spatial constraints of the nucleus
We investigate the role of the highly conserved H2A acidic patch in chromatin remodeling by ISWI enzymes
We find that the acidic patch is used post-binding in order to activate remodeling by both INO80 and ISWI family remodelers
Summary
Eukaryotic genomes are packaged into chromatin, enabling large amounts of DNA to fit into the spatial constraints of the nucleus. Cells have evolved several sophisticated strategies to regulate chromatin structure at the nucleosome level These include the covalent modification of histone proteins and DNA, as well as non-covalent changes to the position or composition of nucleosomes at specific genomic loci. Many of the non-covalent transformations, ranging from sliding nucleosomes to the complete disassembly of the histone octamer, are catalyzed by ATP-dependent chromatin remodeling enzymes (Zhou et al, 2016). Underscoring their central role in chromatin regulation, remodeling enzymes play essential roles in many processes including transcription, DNA replication, and DNA repair (Falbo and Shen, 2006; Hota and Bruneau, 2016; Price and D’Andrea, 2013). How a relatively small number of remodeler types carry out such diverse regulatory functions remains an area of active research, not least because much
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