PXD062226

PXD062226 is an original dataset announced via ProteomeXchange.

Title	SMARCB1 missense mutants disrupt SWI/SNF complex stability and remodeling activity
Description	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 SMARCB1 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 SMARCB1, 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 SMARCB1’s mutational landscape and its implications for cancer diagnostics.
HostingRepository	PRIDE
AnnounceDate	2026-02-23
AnnouncementXML	Submission_2026-02-23_09:07:03.051.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Garrett Cooper
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2025-03-25 14:20:42	ID requested
⏵ 1	2026-02-23 09:07:03	announced

Dataset with its publication pending

submitter keyword: SWI/SNF, SMARCB1, chromatin, complex stability,Cancer

Andrew Hong
contact affiliation	Emory Univerity
contact email	andrew.hong2@emory.edu
lab head
Garrett Cooper
contact affiliation	Emory University
contact email	gcooper.gene@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD062226
     1. Label: PRIDE project
     2. Name: SMARCB1 missense mutants disrupt SWI/SNF complex stability and remodeling activity