Comprehensive Characterization of the Coding and Non-Coding Single Nucleotide Polymorphisms in the Tumor Protein p63 (TP63) Gene Using In Silico Tools.

Md. Ismail Hosen,Md. Ackas Ali,Shafaat Hossain,Hossain Uddin Shekhar,Shamima Akter

doi:10.3390/biom11111733

Abstract

Single nucleotide polymorphisms (SNPs) help to understand the phenotypic variations in humans. Genome-wide association studies (GWAS) have identified SNPs located in the tumor protein 63 (TP63) locus to be associated with the genetic susceptibility of cancers. However, there is a lack of in-depth characterization of the structural and functional impacts of the SNPs located at the TP63 gene. The current study was designed for the comprehensive characterization of the coding and non-coding SNPs in the human TP63 gene for their functional and structural significance. The functional and structural effects of the SNPs were investigated using a wide variety of computational tools and approaches, including molecular dynamics (MD) simulation. The deleterious impact of eight nonsynonymous SNPs (nsSNPs) affecting protein stability, structure, and functions was measured by using 13 bioinformatics tools. These eight nsSNPs are in highly conserved positions in protein and were predicted to decrease protein stability and have a deleterious impact on the TP63 protein function. Molecular docking analysis showed five nsSNPs to reduce the binding affinity of TP63 protein to DNA with significant results for three SNPs (R319H, G349E, and C347F). Further, MD simulations revealed the possible disruption of TP63 and DNA binding, hampering the essential protein function. PolymiRTS study found five non-coding SNPs in miRNA binding sites, and the GTEx portal recognized five eQTLs SNPs in single tissue of the lung, heart (LV), and cerebral hemisphere (brain). Characterized nsSNPs and non-coding SNPs will help researchers to focus on TP63 gene loci and ascertain their association with certain diseases.

Highlights

Human tumor protein 63 is encoded by the TP63 gene, which is 4944 bp (4.94 kb) long and located in chromosome 3 at the 3q28 locus
A variety of tools were selected for computational analysis of the nonsynonymous single nucleotide polymorphisms (SNPs) (nsSNPs) of TP63
The results show that all of the miRNA target sites for miRNA predicted to be disrupted by SNPs in TP63 were obtained from CLASH experimental data (N)

Summary

Introduction

Human tumor protein 63 is encoded by the TP63 gene, which is 4944 bp (4.94 kb) long and located in chromosome 3 at the 3q28 locus. It has 12 isoforms listed in the UniProt database. TP63 isoform 1 is 680 amino acids long and acts as a transcription factor (TF) that regulates gene expressions in multiple pathways, notably in tumorigenesis and development [1]. TP63 plays an essential role in the development of the body’s organs and tissues. Aside from its developmental roles, the p63 protein appears to be required for the preservation of various cells and tissues in late age. TP63 shares sequence similarity with the tumor suppressor p53 family, with cellular homeostasis, development, differentiation, and growth control as the crucial functions [3,4]

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