missense mutants disrupt SWI/SNF complex stability and remodeling activity.

Research square
Authors
Abstract

Chromatin remodeling complexes, such as the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, play key roles in regulating gene expression by modulating nucleosome positioning. The core subunit SMARCB1 is essential for these functions, as it anchors the complex to the nucleosome acidic patch, enabling effective chromatin remodeling. While biallelic inactivation of is a hallmark of several aggressive pediatric malignancies, the functional implication of missense mutations is not fully understood. Current diagnostic approaches focus on detecting the presence or absence of SMARCB1 by immunohistochemistry (IHC) often without consideration of mutation status as such data is lacking. Here, we present the first comprehensive deep mutational scanning (DMS) of , encompassing 8,418 amino acid substitutions, to systematically assess their functional impact. We show that missense mutations in the RPT2 domain of SMARCB1 disrupt SMARCB1 tumor suppressor function by destabilizing the SWI/SNF complex. Notably, we identify mutations in RPT2 that impair chromatin remodeling and transcriptional regulation to an extent comparable to nonsense mutations, despite maintaining detectable protein expression, thus challenging the conventional diagnostic reliance on IHC. Importantly, these mutations seem to act by disrupting winged-helix domain flexibility. These findings provide a deeper understanding of the role of SMARCB1 in chromatin remodeling and cancer biology, highlighting the limitations of current mutation classification approaches. By establishing a high-throughput functional framework, this study offers a critical resource for elucidating 's mutational landscape and its implications for cancer diagnostics.

Year of Publication
2025
Journal
Research square
Date Published
03/2025
ISSN
2693-5015
DOI
10.21203/rs.3.rs-6018128/v1
PubMed ID
40196006
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