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Cancer-associated polybromo-1 bromodomain 4 missense variants variably impact bromodomain ligand binding and cell growth suppression.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2024 Apr; Vol. 300 (4), pp. 107146. Date of Electronic Publication: 2024 Mar 07. - Publication Year :
- 2024
-
Abstract
- The polybromo, brahma-related gene 1-associated factors (PBAF) chromatin remodeling complex subunit polybromo-1 (PBRM1) contains six bromodomains that recognize and bind acetylated lysine residues on histone tails and other nuclear proteins. PBRM1 bromodomains thus provide a link between epigenetic posttranslational modifications and PBAF modulation of chromatin accessibility and transcription. As a putative tumor suppressor in several cancers, PBRM1 protein expression is often abrogated by truncations and deletions. However, ∼33% of PBRM1 mutations in cancer are missense and cluster within its bromodomains. Such mutations may generate full-length PBRM1 variant proteins with undetermined structural and functional characteristics. Here, we employed computational, biophysical, and cellular assays to interrogate the effects of PBRM1 bromodomain missense variants on bromodomain stability and function. Since mutations in the fourth bromodomain of PBRM1 (PBRM1-BD4) comprise nearly 20% of all cancer-associated PBRM1 missense mutations, we focused our analysis on PBRM1-BD4 missense protein variants. Selecting 16 potentially deleterious PBRM1-BD4 missense protein variants for further study based on high residue mutational frequency and/or conservation, we show that cancer-associated PBRM1-BD4 missense variants exhibit varied bromodomain stability and ability to bind acetylated histones. Our results demonstrate the effectiveness of identifying the unique impacts of individual PBRM1-BD4 missense variants on protein structure and function, based on affected residue location within the bromodomain. This knowledge provides a foundation for drawing correlations between specific cancer-associated PBRM1 missense variants and distinct alterations in PBRM1 function, informing future cancer personalized medicine approaches.<br />Competing Interests: Conflict of interest The authors declare they have no conflicts of interest with the contents of this article.<br /> (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Cell Proliferation
Ligands
Nuclear Proteins genetics
Nuclear Proteins metabolism
Nuclear Proteins chemistry
Protein Binding
Models, Molecular
Protein Structure, Tertiary
DNA-Binding Proteins metabolism
DNA-Binding Proteins genetics
DNA-Binding Proteins chemistry
Mutation, Missense
Neoplasms genetics
Neoplasms metabolism
Neoplasms pathology
Protein Domains
Transcription Factors genetics
Transcription Factors metabolism
Transcription Factors chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 300
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38460939
- Full Text :
- https://doi.org/10.1016/j.jbc.2024.107146