Abstract：
MDC1 (Mediator of DNA damage Checkpoint protein 1) functions to facilitate the localization of numerous DNA damage response (DDR) components to DNA double-strand break sites. MDC1 is an integral component in preserving genomic stability and appropriate DDR regulation. There haven\'t been systematic investigations of MDC1 mutations that induce cancer and genomic instability. Variations in nsSNPs have the potential to modify the protein chemistry and their function. Describing functional SNPs in disease-associated genes presents a significant conundrum for investigators, it is possible to assess potential functional SNPs before conducting larger population examinations. Multiple sequences and structure-based bioinformatics strategies were implemented in the current in-silico investigation to discern potential nsSNPs of the MDC1 genes. The nsSNPs were identified with SIFT, SNAP2, Align GVGD, PolyPhen-2, and PANTHER, and their stability was determined with MUpro. The conservation, solvent accessibility, and structural effects of the mutations were identified with ConSurf, NetSurfP-2.0, and SAAFEC-SEQ respectively. Cancer-related analysis of the nsSNPs was conducted using cBioPortal and TCGA web servers. The present study appraised five nsSNPs (P1426T, P69S, P194R, P203L, and H131Y) as probably mutilating due to their existence in highly conserved regions and propensity to deplete protein stability. The nsSNPs P194R, P203L, and H131Y were concluded as deleterious and possibly damaging from the 5 prediction tools. The functional nsSNP P194R mutation is associated with skin cutaneous melanoma while no significant records were found for other nsSNPs. The present study concludes that the highly deleterious P194R mutations can potentially induce genomic instability and contribute to various cancers\' pathogenesis. Developing drugs targeting these mutations can undoubtedly be advantageous in large population-based studies, particularly in the development of precision medicine.
摘要：
MDC1（DNA损伤检查点蛋白1的介体）的功能是促进许多DNA损伤反应（DDR）成分定位到DNA双链断裂位点。MDC1是保持基因组稳定性和适当DDR调节的组成部分。尚未对诱导癌症和基因组不稳定性的MDC1突变进行系统研究。nsSNP的变化具有改变蛋白质化学及其功能的潜力。描述疾病相关基因中的功能性SNP对研究人员提出了一个重要的难题，在进行更大规模的人群检查之前,有可能评估潜在的功能性SNP.在当前的计算机研究中实施了多种基于序列和结构的生物信息学策略，以辨别MDC1基因的潜在nsSNP。nsSNP用SIFT鉴定，SNAP2,对齐GVGD,PolyPhen-2和PANTHER,用MUpro测定其稳定性。保护，溶剂可及性,用ConSurf鉴定了突变的结构效应，分别为NetSurfP-2.0和SAAFEC-SEQ。使用cBioPortal和TCGA网络服务器进行nsSNP的癌症相关分析。本研究评估了五个nsSNP(P1426T，P69S,P194R,P203L,和H131Y）可能是由于它们存在于高度保守的区域中并且倾向于消耗蛋白质稳定性。nsSNPsP194R，P203L,从5种预测工具中，H131Y被认为是有害的，可能是有害的。功能性nsSNPP194R突变与皮肤皮肤黑色素瘤有关，而其他nsSNP则没有发现明显的记录。本研究得出结论，高度有害的P194R突变可能导致基因组不稳定，并有助于各种癌症的发病机制。开发针对这些突变的药物在大规模人群研究中无疑是有利的。特别是在精准医学的发展方面。
