Hossen Md Arif, Jahan Umme Mim Sad, Hossain Md Arju, Asif Khalid Hossain, Rahman Ahona, Ahmed Sabbir, Uddin Md Moin, Amin Md Faisal, Barik Muhammad Abdul, Islam Mohammod Johirul, Kamruzzaman Mohammad, Hasnat Soharth, Uddin Mohammad Nasir, Islam Tofazzal, Hoque M Nazmul
Department of Biochemistry and Molecular Biology, Mawlana Bhashani Science and Technology University, Santosh, Tangail, Bangladesh.
Department of Biochemistry and Biotechnology, Khwaja Yunus Ali University, Sirajganj, Bangladesh.
PLoS One. 2025 Jun 10;20(6):e0320550. doi: 10.1371/journal.pone.0320550. eCollection 2025.
Single nucleotide polymorphisms (SNPs) in DNA repair genes can impair protein structure and function, contributing to disease development, including cancer. Non-synonymous SNPs (nsSNPs) in the LIG3 gene are linked to genomic instability and increased cancer risk, particularly acute myeloid leukemia (AML). This study aims to identify the most deleterious nsSNPs in the LIG3 and potential therapeutic targets for DNA repair restoration in AML. We employed different computational approaches to analyze LIG3 nsSNPs and pathogenicity. Subsequently, molecular docking, molecular dynamics simulation (MDS), gene expression and clinical validation of LIG3 were performed to evaluate ligand-binding affinities, protein stability and to identify discriminatory gene signatures. Out of the 12,191 mapped SNPs, 132 were nsSNPs located in the coding region. Among these, 18 nsSNPs were identified as detrimental including 12 destabilizing and 6 stabilizing nsSNPs. Nine cancer-associated nsSNPs, including L381R and R528C, were predicted due to their structural and functional impacts. Further analysis revealed key phosphorylation and methylation sites, such as 529S and 224R. MDS highlighted stable interactions of compounds AHP-MPC and DM-BFC with wild-type and R528C mutant LIG3 proteins, while R671G and V781M mutants showed instability. Protein-protein interaction networks and functional enrichment linked LIG3 to DNA repair pathways. Kaplan-Meier analysis associated high LIG3 expression with improved survival in breast cancer and AML, suggesting its role as a prognostic biomarker. This study emphasizes the mutation-specific effects of LIG3 nsSNPs on protein stability and ligand interactions. We recommend identifying DM-BFC to advance personalized medicine approaches for targeting deleterious variants, following in-vitro and in-vivo validation for AML treatment.
DNA修复基因中的单核苷酸多态性（SNP）可损害蛋白质结构和功能，从而促进包括癌症在内的疾病发展。LIG3基因中的非同义SNP（nsSNP）与基因组不稳定和癌症风险增加有关，尤其是急性髓细胞白血病（AML）。本研究旨在确定LIG3中最具有害性的nsSNP以及AML中DNA修复恢复的潜在治疗靶点。我们采用了不同的计算方法来分析LIG3的nsSNP及其致病性。随后，进行了分子对接、分子动力学模拟（MDS）、LIG3的基因表达和临床验证，以评估配体结合亲和力、蛋白质稳定性并识别具有鉴别性的基因特征。在12191个映射的SNP中，有132个是位于编码区的nsSNP。其中，18个nsSNP被鉴定为有害，包括12个使蛋白不稳定的和6个使蛋白稳定的nsSNP。由于其结构和功能影响，预测了9个与癌症相关的nsSNP，包括L381R和R528C。进一步分析揭示了关键的磷酸化和甲基化位点，如529S和224R。MDS突出了化合物AHP-MPC和DM-BFC与野生型和R528C突变型LIG3蛋白的稳定相互作用，而R671G和V781M突变体则表现出不稳定性。蛋白质-蛋白质相互作用网络和功能富集将LIG3与DNA修复途径联系起来。Kaplan-Meier分析表明，LIG3高表达与乳腺癌和AML患者生存率提高相关，提示其作为预后生物标志物的作用。本研究强调了LIG3 nsSNP对蛋白质稳定性和配体相互作用的突变特异性影响。我们建议鉴定出DM-BFC，以便在对AML治疗进行体外和体内验证后，推进针对有害变体的个性化医疗方法。
