Structural Dynamics, Molecular Alterations, and Oncogenic Correlationsof High-Risk nsSNPs in DNMT3A Gene

Introduction: Single-nucleotide polymorphisms (SNPs), particularly nonsynonymous SNPs (nsSNPs), are common genetic variations that can significantly impact protein structure and function. DNMT3A, a key DNA methyltransferase, is crucial for epigenetic regulation through cytosine methylation. Mutations in DNMT3A, especially nsSNPs, are linked to cancer development. This study focuses on identifying deleterious nsSNPs in DNMT3A using computational tools to understand their potential role in tumorigenesis. Methods: A total of 1,215 nsSNPs in DNMT3A were collected from the dbSNP database and analyzed using seven prediction tools: SIFT, PROVEAN, Align-GVGD, PANTHERcSNP, MutPred, MuPro, and I-Mutant 3.0. Conserved and surface-exposed residues were assessed with NetSurfP. Molecular dynamics simulations were used to study structural differences between wild-type and mutant DNMT3A. Gene expression and survival analyses were also conducted to explore cancer associations. Results: Five nsSNPs—Y735C, R749P, L547P, I780T, and L637P—were consistently predicted to be deleterious. Among them, R749P was found to be highly conserved and exposed, suggesting a functional role in protein interactions. Molecular dynamics revealed reduced flexibility in the R749P mutant, indicating structural alteration. DNMT3A was found to be upregulated in UCEC and SKCM, with high expression correlating with poor survival in UCEC. Discussion: The identified nsSNPs, especially R749P, likely affect DNMT3A’s stability and function. The structural rigidity caused by R749P may interfere with its methylation activity, contributing to cancer development. The observed expression patterns in UCEC and SKCM support its potential role as a biomarker or therapeutic target. Conclusion: This study highlights critical nsSNPs in DNMT3A, with R749P showing strong structural and functional impacts. The findings provide insights into DNMT3A’s role in cancer and offer a basis for further experimental validation and drug development.