XRCC5 非同义单核苷酸多态性 (nsSNPs) 在急性髓性白血病预后中的内测分析

IF 1 Q4 GENETICS & HEREDITY

Gene Reports Pub Date : 2024-11-20 DOI:10.1016/j.genrep.2024.102090

Md. Arif Hossen , Md. Arju Hossain , Mohammad Kamruzzaman , Fahim Alam Nobel , Md. Moin Uddin , Md. Tanvir Hossain , Numan Bin Taz , Shahidullah , Tumpa Rani Sarker , Rafia Tabassum Farin , Abdullah Al Noman , Mohammad Nasir Uddin , Mohammod Johirul Islam

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引用次数: 0

摘要

X 射线修复交叉互补 5（XRCC5）基因在经典的非同源末端连接（NHEJ）途径中发挥着关键作用，进一步应对 DNA 双链断裂。我们的研究旨在探索 XRCC5 基因编码区内有害的非同义单核苷酸多态性（nsSNPs），这些多态性可能会影响蛋白质功能并影响癌症进展。我们利用多种计算方法研究了人类 XRCC5 基因中潜在的有害 nsSNPs，以了解它们对蛋白质结构和功能的影响。在 XRCC5 基因中发现的 412 个错义变异、42 个错义和体细胞 nsSNPs 中，有两个（Y316C 和 R643W）可能是有害的。通过 HOPE 项目进行的分析强调了野生型和突变型氨基酸之间在理化性质、结构变化和保守结构域内突变方面的显著差异。此外，我们还利用 GPS-MSP 1.0 和 NetPhos 3.1 服务器分别确定了 XRCC5 蛋白上的甲基化位点（R486）和磷酸化位点（318S 和 333Y）。CID: 348883 (-9.1 kcal/mol)、CID: 376106 (-8.9 kcal/mol)、CID: 381764 (-8.8 kcal/mol) 和 CID: 402650 (-8.7 kcal/mol)这四种具有药理学意义的化合物显示出与突变蛋白的强大结合亲和力。与野生型蛋白相比，突变型 XRCC5 蛋白的结合亲和力降低已被确定会影响耐药性。此外，分子动力学模拟研究表明，Y316C 和 R643W 突变可能会影响 XRCC5 蛋白的结构完整性，限制其保持正确构象的能力。最后，Kaplan-Meier绘图仪研究表明，XRCC5基因表达的改变会显著影响不同癌症类型患者的生存率。最后，该研究在 XRCC5 蛋白中发现了两个高度有害的 nsSNPs，它们有助于进一步的蛋白质组和基因组研究，从而促进疾病的诊断和治疗。

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In-silico analysis of XRCC5 non-synonymous single nucleotide polymorphisms (nsSNPs) in acute myeloid leukemia prognosis

The X-ray repair cross-complementing 5 (XRCC5) gene plays a pivotal role in the classical non-homologous end joining (NHEJ) pathway further responding to DNA double-strand breaks. Our study aims to explore harmful non-synonymous single nucleotide polymorphisms (nsSNPs) within the coding region of the XRCC5 gene, potentially impacting protein function and influencing cancer progression. We utilized several computational methods to examine potential harmful nsSNPs within the human XRCC5 gene to understand their influence on protein structure and function. Out of 412 missense variants, the 42 missense and somatic nsSNPs identified in the XRCC5 gene, two (Y316C and R643W) were found to be potentially harmful. Analysis through Project HOPE highlighted significant differences in physicochemical properties, structural changes, and mutations within conserved domains between wild-type and mutant amino acids. Additionally, we identified a methylation site (R486) and phosphorylation sites (318S and 333Y) on the XRCC5 protein using GPS-MSP 1.0 and NetPhos 3.1 servers, respectively. The four pharmacologically significant compounds, CID: 348883 (−9.1 kcal/mol), CID: 376106 (−8.9 kcal/mol), CID: 381764 (−8.8 kcal/mol) and CID: 402650 (−8.7 kcal/mol) demonstrate strong binding affinity to the mutant proteins. Decreased binding affinity to mutant XRCC5 proteins compared to wild-type protein has been determined to influence drug resistance. Besides, molecular dynamics simulation studies demonstrated that the Y316C and R643W mutations are likely to affect the structural integrity of the XRCC5 protein, limiting its capacity to retain correct conformation. Ultimately, examination through the Kaplan-Meier plotter study demonstrated that alterations in XRCC5 gene expression significantly impact the survival rates of patients across various cancer types. Finally, the study found two highly deleterious nsSNPs in the XRCC5 protein that can be helpful for further proteomic and genomic studies for disease diagnosis and treatment.

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来源期刊

Gene Reports Biochemistry, Genetics and Molecular Biology-Genetics

CiteScore

3.30

自引率

7.70%

发文量

246

审稿时长

49 days

期刊介绍： Gene Reports publishes papers that focus on the regulation, expression, function and evolution of genes in all biological contexts, including all prokaryotic and eukaryotic organisms, as well as viruses. Gene Reports strives to be a very diverse journal and topics in all fields will be considered for publication. Although not limited to the following, some general topics include: DNA Organization, Replication & Evolution -Focus on genomic DNA (chromosomal organization, comparative genomics, DNA replication, DNA repair, mobile DNA, mitochondrial DNA, chloroplast DNA). Expression & Function - Focus on functional RNAs (microRNAs, tRNAs, rRNAs, mRNA splicing, alternative polyadenylation) Regulation - Focus on processes that mediate gene-read out (epigenetics, chromatin, histone code, transcription, translation, protein degradation). Cell Signaling - Focus on mechanisms that control information flow into the nucleus to control gene expression (kinase and phosphatase pathways controlled by extra-cellular ligands, Wnt, Notch, TGFbeta/BMPs, FGFs, IGFs etc.) Profiling of gene expression and genetic variation - Focus on high throughput approaches (e.g., DeepSeq, ChIP-Seq, Affymetrix microarrays, proteomics) that define gene regulatory circuitry, molecular pathways and protein/protein networks. Genetics - Focus on development in model organisms (e.g., mouse, frog, fruit fly, worm), human genetic variation, population genetics, as well as agricultural and veterinary genetics. Molecular Pathology & Regenerative Medicine - Focus on the deregulation of molecular processes in human diseases and mechanisms supporting regeneration of tissues through pluripotent or multipotent stem cells.