García-Ayala Fernando Daniel, Ayala-Madrigal María de la Luz, Peregrina-Sandoval Jorge, Moreno-Ortiz José Miguel, González-Mercado Anahí, Gutiérrez-Angulo Melva
Instituto de Genética Humana "Dr. Enrique Corona Rivera", Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico.
Programa de Doctorado en Genética Humana, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico.
Int J Mol Sci. 2025 Aug 1;26(15):7455. doi: 10.3390/ijms26157455.
The 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 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 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.
该基因在多种癌症类型中频繁发生突变，通过其蛋白质p53在调节细胞周期和细胞凋亡中起关键作用。意义未明的错义变异（VUSs）在理解其对蛋白质功能的影响方面带来挑战，并使临床解读复杂化。本研究旨在分析gnomAD数据库中报告的p53错义VUSs的影响，特别关注其对蛋白质稳定性和磷酸化的影响。在本研究中，使用包括PhosphositePlus v6.7.4、Kinase Library v0.0.11和Dynamut2在内的计算机工具分析了gnomAD数据库中报告的33个p53错义VUSs。在这些分析的变异中，五个破坏了已知的磷酸化位点，而另外五个产生了新的磷酸化共有序列。此外，20个变异对蛋白质结构表现出中等程度的去稳定化作用。至少三个错义VUSs被鉴定为可能影响p53功能，这可能有助于癌症发展。这些发现突出了整合计算机结构和功能分析以评估错义VUSs致病潜力的重要性。
