The Graduate School of Engineering and Natural Science, Istanbul Medipol University, 34810 Istanbul, Turkey.
Department of Computer Engineering, Muğla Sıtkı Koçman University, 48000 Muğla, Turkey.
Biomolecules. 2020 Apr 28;10(5):680. doi: 10.3390/biom10050680.
Cancer is the second leading cause of death worldwide. The etiology of the disease has remained elusive, but mutations causing aberrant RNA splicing have been considered one of the significant factors in various cancer types. The association of aberrant RNA splicing with drug/therapy resistance further increases the importance of these mutations. In this work, the impact of the splicing factor 3B subunit 1 (SF3B1) K700E mutation, a highly prevalent mutation in various cancer types, is investigated through molecular dynamics simulations. Based on our results, K700E mutation increases flexibility of the mutant SF3B1. Consequently, this mutation leads to i) disruption of interaction of pre-mRNA with SF3B1 and p14, thus preventing proper alignment of mRNA and causing usage of abnormal 3' splice site, and ii) disruption of communication in critical regions participating in interactions with other proteins in pre-mRNA splicing machinery. We anticipate that this study enhances our understanding of the mechanism of functional abnormalities associated with splicing machinery, thereby, increasing possibility for designing effective therapies to combat cancer at an earlier stage.
癌症是全球第二大死亡原因。尽管该疾病的病因仍未明确，但导致 RNA 剪接异常的突变已被认为是各种癌症类型的重要因素之一。RNA 剪接异常与药物/治疗耐药性的关联进一步增加了这些突变的重要性。在这项工作中，通过分子动力学模拟研究了剪接因子 3B 亚基 1（SF3B1）K700E 突变的影响，该突变在各种癌症类型中非常普遍。根据我们的结果，K700E 突变增加了突变 SF3B1 的柔韧性。因此，这种突变导致：i）前体 mRNA 与 SF3B1 和 p14 的相互作用被破坏，从而阻止 mRNA 正确排列并导致异常 3' 剪接位点的使用，ii）在参与前体 mRNA 剪接机制中与其他蛋白质相互作用的关键区域的通信被破坏。我们预计，这项研究将增强我们对与剪接机制相关的功能异常机制的理解，从而增加在早期阶段设计有效治疗癌症的可能性。
