ATP-dependent chromatin remodelling complexes (CRCs) are large multi-subunit machines required in all eukaryotes to overcome the barrier presented by the tight packaging of DNA into nucleosomes. By harnessing the energy released from ATP hydrolysis to mobilise target nucleosomes, CRCs provide DNA access to the factors responsible for transcription, DNA repair, replication and recombination. Whereas the yeast SWI/SNF chromatin remodelling complex is primarily involved with stimulating transcription at inducible target genes, the mammalian counterpart of yeast SWI/SNF, the Brahma associated factor (BAF) complex, plays a fundamental role in the establishment of tissue- and developmental stage-specific transcriptional programs. In fully-developed mammals, the BAF complex also acts as an important global tumour suppressor. In recent years, cancer-cell genome sequencing studies have shown that mutations affecting BAF complex subunits are found in a staggering 20% of all human tumours. BAF complex mutations are particularly frequent in cases of Melanoma (39%), Colorectal (55%) and Ovarian clear-cell (75%) tumours.

Despite these fundamental developmental and tumour suppressor activities, surprisingly little is known about the subunit organisation, molecular structure, target-gene recruitment and functional regulation of the SWI/SNF-family complexes. We are using an interdisciplinary approach comprising yeast genetics, biophysical analysis, in vitro reconstitution, mass spectrometry, x-ray crystallography and cryo-electron microscopy to shed light on the structure and functional mechanism of this important family of macromolecular machines. In doing so we strive to lay the foundations for future chemotherapeutic development to target mutant complexes in a range of human pathologies.

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