■端粒的选择性延长(ALT)途径代表了端粒维持的非规范机制,其独立于常规端粒酶活性而起作用。这三种具有生物学意义的蛋白质,命名为SMARCAL1(SWI/SNF相关的基质相关肌动蛋白依赖性染色质亚家族A样蛋白1调节因子),DAXX(死亡域相关蛋白6)和ATRX(α-地中海贫血/智力低下,X连锁)与某些癌症类型的ALT相关。这项研究的目的是确定这三个基因中最高风险的nsSNP(非同义单核苷酸多态性),并评估它们对它们编码的蛋白质的结构和功能的影响。
■报告的SMARCAL1、DAXX和ATRX基因的遗传多态性从Ensembl数据库中检索。稍后,各种计算工具,如PROVEAN,Polyphen2,SNPs和GO,SNAP2,预测-SNP,黑豹和PMut被用来预测最有害的nsSNP。MutPred被用来理解那些nsSNP有害的潜在分子原因,然后使用ModPred预测翻译后修饰位点(PTM)。使用I-突变体和MUpro来预测SNP对能量稳定性的影响。稍后,使用Mutation3D服务器进行3D聚类分析。此外,ConSurf用于鉴定野生型氨基酸的保守性得分。此外,使用NCBI保守结构域搜索工具来精确定位这三种蛋白质中的保守结构域.希望工程帮助生物物理验证,然后通过使用遗传躁狂症预测这些基因的相互作用和功能。
■对SMARCAL1蛋白的分析显示,在665个nsSNPs中,四个被确定为最有害的:L578S,T581S,P582A,P582S同样,在DAXX蛋白中,在480个nsSNP的池中,P284S,R230C,和R230S被发现是最有害的变体。在ATRX蛋白的情况下,V178D,R246C,和V277G,在总共1009个nsSNP中,被预测是最有害的。发现所有这些nsSNP发生在蛋白质结构域内100%保守的残基位置,并且预测从结构和功能观点来看最具破坏性,并且对它们相应的蛋白质高度不稳定。
■通过不同的生物信息学分析工具对3种蛋白质-SMARCAL1,DAXX和ATRX的计算研究得出的结论是,这些蛋白质的已鉴定的高风险nsSNP是致病性SNP。这些变体可能会产生功能和结构影响,因此使它们成为未来遗传研究的有价值的候选人。
UNASSIGNED: The Alternative Lengthening of Telomeres (ALT) pathway represents a non-canonical mechanism of telomere maintenance that operates independently of the conventional telomerase activity. The three biologically significant proteins, designated as SMARCAL1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1), DAXX (Death domain-associated protein 6) and
ATRX (alpha-thalassemia/mental retardation, X-linked) are associated with ALT in certain cancer types. The purpose of this study was to identify the most high-risk nsSNPs (non-synonymous Single Nucleotide Polymorphisms) within these three genes and assess their impacts on the structure and function of the proteins they encode.
UNASSIGNED: The reported genetic polymorphisms of SMARCAL1, DAXX and
ATRX genes were retrieved from the Ensembl database. Later, various computational tools like PROVEAN, PolyPhen2, SNPs and GO, SNAP2, Predict-SNP, Panther and PMut were used to predict the most deleterious nsSNPs. MutPred was used to understand the underlying molecular reasons of those nsSNPs being deleterious, followed by prediction of Post Translational Modification Sites (PTMs) using ModPred. I-Mutant and MUpro were used to predict the effect of SNP on energy stability. Later, 3D clustering analysis was done using Mutation 3D server. Moreover, ConSurf was utilized to identify the conservation scores of wild-type amino acids. Additionally, the NCBI conserved domain search tool was employed to pinpoint conserved domains within these three proteins. Project-Hope helped for biophysical validation, followed by prediction of these genes\' interaction and function by using GeneMANIA.
UNASSIGNED: Analysis on SMARCAL1 protein revealed that among 665 nsSNPs, four were identified as the most deleterious: L578S, T581S, P582A, and P582S. Similarly, within the DAXX protein, among a pool of 480 nsSNPs, P284S, R230C, and R230S were found out to be the most deleterious variants. In case of
ATRX protein, V178D, R246C, and V277G, from the total of 1009 nsSNPs, were predicted to be the most deleterious. All these nsSNPs were found to occur at residue positions that are 100 % conserved within protein domains and were predicted to be most damaging from both structural and functional perspectives and highly destabilizing to their corresponding proteins.
UNASSIGNED: Computational investigation on the 3 proteins-SMARCAL1, DAXX and
ATRX through different bioinformatics analysis tools concludes that the identified high risk nsSNPs of these proteins are pathogenic SNPs. These variants potentially exert functional and structural influences, thus making them valuable candidates for future genetic studies.