Computational prediction and analysis of deleterious cancer associated missense mutations in DYNC1H1

Abstract

Dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) gene encodes a subunit of human cytoplasmic dynein complex, which has several crucial functions in the cell, such as intracellular transport of DNA damage proteins and mitotic spindle positioning. Recent studies reported the altered expression of DYNC1H1 in different cancers and DYNC1H1 was suggested to be potential biomarker in colorectal cancers. Previously, DYNC1H1 mutations have been associated with neurodegenerative diseases, however mutations of DYNC1H1 have not been fully investigated in cancers except for different types of pancreatic cancers. In this study we aimed to identify the cancer related mutations in DYNC1H1, which are deleterious for the DYNC1H1 structure and/or function. We investigated 523 cancer related missense mutations in DYNC1H1, which were collected from COSMIC database, to predict the effect of mutations on DYNC1H1 function. Of the 523 mutations, we identified 28 amino acid substitutions, which were predicted to be deleterious by PredictSNP1.0. When we searched for the effect of 28 deleterious mutations on protein stability by MUpro and I-Mutant2.0, we observed that most of the mutations decrease the protein stability. We analyzed the localization of deleterious mutations on primary protein structure and identified that predicted deleterious mutations were mainly located in the motor domain, which is crucial for the DYNC1H1 function. In addition, we detected close positioning of mutated residues in AAA + regions on 3D structure by STRUM and UCSF Chimera. When we searched the mutations in COSMIC database, we observed the occurrence of the mutations in different cancers, which might show the importance of these regions in corresponding cancers. Therefore, our findings provide potential structural and functional mutations and hotspots for DYNC1H1.

Keywords: Cancer; Missense mutation; Prediction; Protein function; Protein stability.