The SWI/SNF Subunit INI1 Contains an N-Terminal Winged Helix DNA Binding Domain that Is a Target for Mutations in Schwannomatosis

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

doi:10.1016/j.str.2015.04.021

Abstract

SummarySWI/SNF complexes use the energy of ATP hydrolysis to remodel chromatin. In mammals they play a central role in regulating gene expression during differentiation and proliferation. Mutations in SWI/SNF subunits are among the most frequent gene alterations in cancer. The INI1/hSNF5/SMARCB1 subunit is mutated in both malignant rhabdoid tumor, a highly aggressive childhood cancer, and schwannomatosis, a tumor-predisposing syndrome characterized by mostly benign tumors of the CNS. Here, we show that mutations in INI1 that cause schwannomatosis target a hitherto unidentified N-terminal winged helix DNA binding domain that is also present in the BAF45a/PHF10 subunit of the SWI/SNF complex. The domain is structurally related to the SKI/SNO/DAC domain, which is found in a number of metazoan chromatin-associated proteins.

Highlights

Enzymes that use the energy of ATP hydrolysis to remodel chromatin play a central role in regulating eukaryotic gene expression (Narlikar et al, 2013)
Germline alterations of the gene coding for INI1, one of the core subunits of the complex, predispose individuals to rhabdoid tumors, highly aggressive cancers primarily affecting young children (Versteege et al, 1998)
Mutations in the INI1 gene cause the tumor suppressor syndrome schwannomatosis, which is characterized by mostly benign tumors of the CNS that typically develop in the second or third decade of life (Hulsebos et al, 2007)

Summary

Introduction

Enzymes that use the energy of ATP hydrolysis to remodel chromatin play a central role in regulating eukaryotic gene expression (Narlikar et al, 2013). SWI/SNF chromatin-remodeling complexes were first identified in yeast, but have subsequently been found in all eukaryotic linages. Mutations in SWI/SNF subunits are frequently associated with cancer (Masliah-Planchon et al, 2015). Germline alterations (mutations or deletions) of the gene coding for INI1 ( referred to as hSNF5 due to its similarity to the yeast protein SNF5, SMARCB1, or BAF47), one of the core subunits of the complex, predispose individuals to rhabdoid tumors, highly aggressive cancers primarily affecting young children (Versteege et al, 1998). Mutations within the INI1 gene that are linked to schwannomatosis, in contrast, are missense mutations and in-frame deletions affecting residues in the N-terminal portion of the protein (Bacci et al, 2010; Christiaans et al, 2011; Hadfield et al, 2008; Smith et al, 2012b, 2014). Several of the mutant proteins have been shown to retain some activity (Smith et al, 2012a)

Results

Discussion

Conclusion