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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
GnomAD Missense Variants of Uncertain Significance: Implications for p53 Stability and Phosphorylation
Fernando Daniel García-Ayala1,2, María de la Luz Ayala-Madrigal1,2, Jorge Peregrina-Sandoval2,3
1Instituto de Genética Humana "Dr. Enrique Corona Rivera", Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico.
Abstract:
The TP53 gene, frequently mutated across multiple cancer types, plays a pivotal role in regulating the cell cycle and apoptosis through its protein, p53. Missense variants of uncertain significance (VUSs) in TP53 present challenges in understanding their impact on protein function and complicate clinical interpretation. This study aims to analyze the effects of missense VUSs in p53, as reported in the gnomAD database, with a specific focus on their impact on protein stability and phosphorylation. In this study, 33 missense VUSs in TP53 reported in the gnomAD database were analyzed using in silico tools, including PhosphositePlus v6.7.4, the Kinase Library v0.0.11, and Dynamut2. Of these analyzed variants, five disrupted known phosphorylation sites, while another five created new consensus sequences for phosphorylation. Moreover, 20 variants exhibited a moderate destabilizing effect on the protein structure. At least three missense VUSs were identified as potentially affecting p53 function, which may contribute to cancer development. These findings highlight the importance of integrating in silico structural and functional analysis to assess the pathogenic potential of missense VUSs.
Insights
TP53 gene variants of uncertain significance (VUSs) can impact p53 protein stability and phosphorylation. In silico analysis identified VUSs affecting phosphorylation and protein structure, potentially contributing to cancer development.
Area of Science:
- Genetics
- Molecular Biology
- Bioinformatics
Background:
- The TP53 gene is frequently mutated in various cancers, regulating cell cycle and apoptosis via p53 protein.
- Missense variants of uncertain significance (VUSs) in TP53 pose challenges for clinical interpretation due to unknown functional impact.
Purpose of the Study:
- To analyze the effects of TP53 missense VUSs from the gnomAD database on p53 protein stability and phosphorylation.
- To assess the potential pathogenicity of these VUSs using in silico tools.
Main Methods:
- Analysis of 33 TP53 missense VUSs using in silico tools: PhosphositePlus, Kinase Library, and Dynamut2.
- Evaluation of effects on protein phosphorylation sites and structural stability.
Main Results:
- Five VUSs disrupted known phosphorylation sites; five created new consensus phosphorylation sequences.
- Twenty variants showed moderate destabilizing effects on protein structure.
- At least three missense VUSs were identified as potentially affecting p53 function.
Conclusions:
- In silico analysis is crucial for evaluating the functional impact and pathogenic potential of TP53 missense VUSs.
- Identified VUSs may contribute to cancer development by altering p53 function.
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