preprints.org > biology and life sciences > biochemistry and molecular biology > doi: 10.20944/preprints202310.0282.v1

Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Version 1 : Received: 4 October 2023 / Approved: 5 October 2023 / Online: 5 October 2023 (11:17:08 CEST)

The MLL1 gene located on chromosome 11q23, is crucial for histone lysine-specific methylation and is frequently implicated in various leukemia types. Despite prior in silico investigations into non-synonymous single nucleotide polymorphisms (nsSNPs) associated with leukemia in the MLL1 gene, there is a dearth of comprehensive studies evaluating their impact on the protein's structure, function, and post-translational modifications. Addressing this, our study screened 2049 nsSNPs from the dbSNP database, identifying 62 high-risk variants. A thorough domain analysis revealed that these nsSNPs are distributed across seven domains of the MLL1 protein, potentially affecting their functions. Our conservation analysis highlighted 31 nsSNPs as deleterious, suggesting their potential effects on protein stability and function. Furthermore, utilizing the MutPred2 tool, we identified mutations affecting metal-binding, protein loop structures, and post-translational modifications, which could alter the MLL1 protein's native functionality. Interaction network analysis underscored the role of MLL1 in hematopoietic cell development, implying that mutations may influence hematological malignancies. Additionally, a subset of non-coding SNPs was found to possess regulatory capabilities, potentially affecting gene expression and chromatin modification. Most significantly, using CScape and CScape-somatic tools, four nsSNPs were predicted to be oncogenic, with two classified as cancer drivers, underscoring their potential role in leukemia development. The oncogenic nsSNP, D2724G, located between the FY-rich N and FY-rich C domain of the MLL1 protein, has raised significant interest due to its potential impact on proteolytic cleavage. Predictive analyses, such as those by Mutpred2, suggest a loss of cleavage at D2724 caused by this mutation, potentially affecting the formation of essential MLL1 fragments, p320 and p180. These fragments play a crucial role in creating a stable multiprotein complex that localizes to a specific subnuclear region. Therefore, mutations like D2724G can potentially alter gene expression patterns, influencing cellular behavior and possibly fostering a cancer-prone environment. In conclusion, our research provides an in-depth assessment of the effects of nsSNPs in the MLL1 gene on leukemia, offering potential avenues for personalized treatment strategies, early detection, prognosis, and a better understanding of hematological malignancy genesis.

MLL1 gene; leukemia; computational algorithms; protein structure; nsSNPs

Biology and Life Sciences, Biochemistry and Molecular Biology

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