Structures and Mechanisms of ATP-dependent Chromatin Remodeling Machines
Chromatin remodeling motors use the energy of ATP to alter nucleosome positions, conformation and composition and thereby regulate how the genome is packaged and acted on. Yet compared to other essential motors such as myosins and helicases, the biochemical mechanisms of chromatin remodelers are poorly understood, limiting an understanding of how their functions are regulated. Our long-term goal is to understand the mechanisms of chromatin remodeling motors at the level at which kinesin and helicase action is understood, so we can analogously derive insights into their biological roles and regulation. We are asking the following general questions:
1. How do chromatin remodeling motors couple ATP hydrolysis to changes in nucleosome conformation?
2. What are the differences in mechanism between remodelers from different classes?
We are comparing and contrasting three classes of chromatin remodelers, the ISWI class, the SWI/SNF class and the INO80 class. These three classes share an evolutionarily related ATPase core but carry out different transformations of chromatin. SWI/SNF complexes generate a distribution of nucleosomal states, which contain nucleosomes with altered positions, altered composition and altered DNA path. These products are thought to enable efficient exposure of short regions of DNA for localized binding of activators or repressors. By contrast, ISWI complexes, slide nucleosomes without disassembling the histone octamer. The nucleosome sliding property of ISWI complexes such as ACF is thought to be important for generating the appropriate chromatin architecture for promoting chromatin compaction and gene silencing. INO80 complexes. At a superficial level the INO80 remodeling complex carries out a similar reaction as the ACF complex, namely sliding nucleosomes. However, the mechanism of INO80 differs substantially from ACF as do its biological functions, which entail regulation of transcription and DNA repair.