Understanding the impact of DIS3 cancer-associated mutations by in silico structure modeling

Abstract

DIS3 gene is reported as a driver gene specifically mutated in a few cancer types including multiple myeloma. Unraveling the molecular effects of DIS3 mutations on protein structure may provide insights into the functional effect of different substitutions. Hence, the aim of this study is to analyze the structural and functional consequences of hotspot mutations in DIS3 by using various sequence and structure-based bioinformatics methods. In addition to sequence-based programs, the effect of hotspot mutations on protein stability and the overall pathogenicity was investigated using SDM and Missense3D. Moreover, mutations were modeled on protein structure using UCSF Chimera. Changes in residue interactions after mutations were investigated using RINalyzer. In total 6 positions in DIS3 are reported as hotspot positions. Our analysis showed all hotspots were located in highly conserved positions and their substitution resulted in clashes or disruption in interaction with the Mg2+ or nucleic acid. Our findings confirmed analysis of the residue interaction network provides a better insight into the functional and structural impact of the DIS3 mutations. We expect our analysis will be used for designing future experimental evaluation of the mutations in DIS3 gene and it will also help evaluate other cancer driver genes' mutations.