Kim Dong-Chul, Kang Mingon, Biswas Ashis, Yang Chin-Rang, Wang Xiaoyu, Gao Jean X
* Department of Computer Science, University of Texas - Rio Grande Valley, Edinburg, TX78539, USA.
† Department of Computer Science, Kennesaw State University, Marietta, GA 30060, USA.
J Bioinform Comput Biol. 2017 Apr;15(2):1750006. doi: 10.1142/S0219720017500068.
Ionizing radiation (IR) causing damages to Deoxyribonucleic acid (DNA) constitutes a broad range of base damage and double strand break, and thereby, it induces the operation of relevant signaling pathways such as DNA repair, cell cycle control, and cell apoptosis. The goal of this paper is to study how the exposure to low dose radiation affects the human body by observing the signaling pathway associated with Ataxia Telangiectasia mutated (ATM) using Reverse-Phase Protein Array (RPPA) and isogenic human Ataxia Telangiectasia (A-T) cells under different amounts and durations of IR exposure. In order to verify which proteins could be involved in a DNA damage-caused pathway, only proteins that highly interact with each other under IR are selected by using correlation coefficient. The pathway inference is derived from learning Bayesian networks in combination with prior knowledge such as Protein-Protein Interactions (PPIs) and signaling pathways from well-known databases. Learning Bayesian networks is based on a score and search scheme that provides the highest scored network structure given a score function, and the prior knowledge is included in the score function as a prior probability by using Dempster-Shafer theory (DST). In this way, the inferred network can be more likely to be similar to already discovered pathways and consistent with confirmed PPIs for more reliable inference. The experimental results show which proteins are involved in signaling pathways under IR, how the inferred pathways are different under low and high doses of IR, and how the selected proteins regulate each other in the inferred pathways. As our main contribution, overall results confirm that low dose IR could cause DNA damage and thereby induce and affect related signaling pathways such as apoptosis, cell cycle, and DNA repair.
电离辐射（IR）对脱氧核糖核酸（DNA）造成损伤，会引发广泛的碱基损伤和双链断裂，进而诱导DNA修复、细胞周期调控和细胞凋亡等相关信号通路的运行。本文的目的是通过使用反相蛋白质阵列（RPPA）和等基因人类共济失调毛细血管扩张症（A-T）细胞，观察与共济失调毛细血管扩张症突变（ATM）相关的信号通路，研究低剂量辐射暴露如何影响人体，辐射暴露的剂量和持续时间各不相同。为了验证哪些蛋白质可能参与DNA损伤引发的通路，通过使用相关系数，只选择在电离辐射下彼此高度相互作用的蛋白质。通路推断是通过结合诸如蛋白质-蛋白质相互作用（PPI）和来自知名数据库的信号通路等先验知识来学习贝叶斯网络得出的。学习贝叶斯网络基于一种评分和搜索方案，该方案在给定评分函数的情况下提供得分最高的网络结构，并且通过使用Dempster-Shafer理论（DST）将先验知识作为先验概率包含在评分函数中。通过这种方式，推断出的网络更有可能与已发现的通路相似，并与已确认的PPI一致，从而进行更可靠的推断。实验结果表明了哪些蛋白质参与电离辐射下的信号通路，在低剂量和高剂量电离辐射下推断出的通路有何不同，以及在推断出的通路中所选蛋白质如何相互调节。作为我们的主要贡献，总体结果证实低剂量电离辐射会导致DNA损伤，从而诱导并影响细胞凋亡、细胞周期和DNA修复等相关信号通路。
