Panchal Nagesh Kishan, Samdani Poorva, Sengupta Tiasa, Prince Sabina Evan
Department of Biotechnology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, 632 014, India.
Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India.
Mol Biotechnol. 2025 Mar;67(3):1201-1221. doi: 10.1007/s12033-024-01120-x. Epub 2024 Mar 15.
Ataxia telangiectasia-mutated (ATM) protein kinase, a key player in cellular integrity regulation, is known for its role in DNA damage response. This study investigates the broader impact of ATM on cellular processes and potential clinical manifestations arising from mutations, aiming to expand our understanding of ATM's diverse functions beyond conventional roles. The research employs a comprehensive set of computational techniques for a thorough analysis of ATM mutations. The mutation data are curated from dbSNP and HuVarBase databases. A meticulous assessment is conducted, considering factors such as deleterious effects, protein stability, oncogenic potential, and biophysical characteristics of the identified mutations. Conservation analysis, utilizing diverse computational tools, provides insights into the evolutionary significance of these mutations. Molecular docking and dynamic simulation analyses are carried out for selected mutations, investigating their interactions with Y2080D, AZD0156, and quercetin inhibitors to gauge potential therapeutic implications. Among the 419 mutations scrutinized, five (V1913C, Y2080D, L2656P, C2770G, and C2930G) are identified as both disease causing and protein destabilizing. The study reveals the oncogenic potential of these mutations, supported by findings from the COSMIC database. Notably, Y2080D is associated with haematopoietic and lymphoid cancers, while C2770G shows a correlation with squamous cell carcinomas. Molecular docking and dynamic simulation analyses highlight strong binding affinities of quercetin for Y2080D and AZD0156 for C2770G, suggesting potential therapeutic options. In summary, this computational analysis provides a comprehensive understanding of ATM mutations, revealing their potential implications in cellular integrity and cancer development. The study underscores the significance of Y2080D and C2770G mutations, offering valuable insights for future precision medicine targeting-specific ATM. Despite informative computational analyses, a significant research gap exists, necessitating essential in vitro and in vivo studies to validate the predicted effects of ATM mutations on protein structure and function.
共济失调毛细血管扩张症突变（ATM）蛋白激酶是细胞完整性调节的关键因子，因其在DNA损伤反应中的作用而闻名。本研究调查了ATM对细胞过程的更广泛影响以及由突变引起的潜在临床表现，旨在扩展我们对ATM除传统作用之外的多种功能的理解。该研究采用了一套全面的计算技术对ATM突变进行深入分析。突变数据来自dbSNP和HuVarBase数据库。进行了细致的评估，考虑了诸如有害效应、蛋白质稳定性、致癌潜力以及所识别突变的生物物理特征等因素。利用多种计算工具进行的保守性分析，揭示了这些突变的进化意义。对选定的突变进行了分子对接和动态模拟分析，研究它们与Y2080D、AZD0156和槲皮素抑制剂的相互作用，以评估潜在的治疗意义。在审查的419个突变中，有五个（V1913C、Y2080D、L2656P、C2770G和C2930G）被确定为既致病又使蛋白质不稳定。该研究揭示了这些突变的致癌潜力，这得到了COSMIC数据库研究结果的支持。值得注意的是，Y2080D与造血和淋巴癌相关，而C2770G与鳞状细胞癌相关。分子对接和动态模拟分析突出了槲皮素对Y2080D的强结合亲和力以及AZD0156对C2770G的强结合亲和力，表明了潜在的治疗选择。总之，这种计算分析提供了对ATM突变的全面理解，揭示了它们在细胞完整性和癌症发展中的潜在影响。该研究强调了Y2080D和C2770G突变的重要性，为未来针对特定ATM的精准医学提供了有价值的见解。尽管有信息丰富的计算分析，但仍存在重大研究差距，需要进行必要的体外和体内研究来验证ATM突变对蛋白质结构和功能的预测影响。
