Computational Exploration of Functional and Structural Impact of Single Nucleotide Changes in DNMT3A Gene among Acute Myeloid Leukemia Patients

Acute myeloid leukemia (AML) is a blood cell malignancy of the myeloid line, characterized by fast proliferation of aberrant cells that build up in the bone marrow and blood, interfering with normal blood cell synthesis. DNMT3A is a DNA methyltransferase that plays a role in DNA methylation, an epigenetic modification associated with gene expression regulation. DNMT3A mutations are frequently found in AML and are associated with poor prognosis. Objective: To evaluate the impact of DNMT3A mutations on protein structure and function, specifically in the context of AML. Methods: SNPs of DNMT3A gene reported in AML (R882P, R882L, R882S, R882G, and R882C) were retrieved from National Centre for Biotechnology Information (NCBI) database and different in silico approaches were used to investigate how these mutations affect protein structure and function. Results: Prediction tools indicated that mutations are pathogenic affecting DNMT3A function and were found in evolutionarily conserved regions.  Protein stability analysis showed that mutations reduce DNMT3A's structural stability, alter secondary structure of the protein, particularly helices, interacts with other proteins and reduce protein-protein affinity. RNA folding analysis revealed abnormal folding patterns caused by mutant, affecting protein translation. DNMT3A expression was reported to be considerably greater in AML compared to normal tissues, and mutations were associated with poor overall survival in AML patients. Methylation levels and post-translational modification sites of DNMT3A were also investigated. Conclusions: Overall, this research highlighted the negative impact of DNMT3A mutations on protein structure and function, emphasizing their importance in the development and prognosis of AML. Acute myeloid leukemia (AML) is a blood cell malignancy of the myeloid line, characterized by fast proliferation of aberrant cells that build up in the bone marrow and blood, interfering with normal blood cell synthesis. DNMT3A is a DNA methyltransferase that plays a role in DNA methylation, an epigenetic modification associated with gene expression regulation. DNMT3A mutations are frequently found in AML and are associated with poor prognosis. Objective: To evaluate the impact of DNMT3A mutations on protein structure and function, specifically in the context of AML. Methods: SNPs of DNMT3A gene reported in AML (R882P, R882L, R882S, R882G, and R882C) were retrieved from National Centre for Biotechnology Information (NCBI) database and different in silico approaches were used to investigate how these mutations affect protein structure and function. Results: Prediction tools indicated that mutations are pathogenic affecting DNMT3A function and were found in evolutionarily conserved regions.  Protein stability analysis showed that mutations reduce DNMT3A's structural stability, alter secondary structure of the protein, particularly helices, interacts with other proteins and reduce protein-protein affinity. RNA folding analysis revealed abnormal folding patterns caused by mutant, affecting protein translation. DNMT3A expression was reported to be considerably greater in AML compared to normal tissues, and mutations were associated with poor overall survival in AML patients. Methylation levels and post-translational modification sites of DNMT3A were also investigated. Conclusions: Overall, this research highlighted the negative impact of DNMT3A mutations on protein structure and function, emphasizing their importance in the development and prognosis of AML.