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

Abstract

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.