SWI/SNF subunit BAF155 N-terminus structure informs the impact of cancer-associated mutations and reveals a potential drug binding site

Mark D Allen,Mark Bycroft,Stefan M V Freund,Giovanna Zinzalla

doi:10.1038/s42003-021-02050-z

Abstract

SWI/SNF (BAF) chromatin remodelling complexes are key regulators of gene expression programs, and attractive drug targets for cancer therapies. Here we show that the N-terminus of the BAF155/SMARCC1 subunit contains a putative DNA-binding MarR-like domain, a chromodomain and a BRCT domain that are interconnected to each other to form a distinct module. In this structure the chromodomain makes interdomain interactions and has lost its canonical function to bind to methylated lysines. The structure provides new insights into the missense mutations that target this module in cancer. This study also reveals two adjacent, highly-conserved pockets in a cleft between the domains that form a potential binding site, which can be targeted with small molecules, offering a new strategy to target SWI/SNF complexes.

Highlights

SWI/SNF (BAF) chromatin remodelling complexes are key regulators of gene expression programs, and attractive drug targets for cancer therapies
Several of the subunits are frequently mutated in a range of cancers. mSWI/SNF complexes have a role in both tumour suppression and oncogenesis, and have emerged as promising targets for cancer therapy[1,2]
Chromodomains can recognize methylated lysine residues in histones, and BRCT domains are found in many proteins that participate in the DNA damage response, suggesting that this region could play an important role in regulating the activity of the complex

Summary

Introduction

SWI/SNF (BAF) chromatin remodelling complexes are key regulators of gene expression programs, and attractive drug targets for cancer therapies. Chromodomains can recognize methylated lysine residues in histones, and BRCT domains are found in many proteins that participate in the DNA damage response, suggesting that this region could play an important role in regulating the activity of the complex. This shows that the this region contains a distinct structural module where the chromodomain, the BRCT domain and a MarR-like domain are interconnected by a complex hydrogen-bond network.

Results

Conclusion