Towards Understanding the Pathogenicity of DROSHA Mutations in Oncohematology.

Dmitrii S Bug,Yuri B Porozov,Natalia V Petukhova,Artem V Tishkov,Ivan S Moiseev

doi:10.3390/cells10092357

Abstract

Myelodysplastic syndrome (MDS) refers to a heterogeneous group of closely related clonal hematopoietic disorders, which are characterized by accumulation of somatic mutations. The acquired mutation burden is suggested to define the pathway and consequent phenotype of the pathology. Recent studies have called attention to the role of miRNA biogenesis genes in MDS progression; in particular, the mutational pressure of the DROSHA gene was determined. Therefore, this highlights the importance of studying the impact of all collected missense mutations found within the DROSHA gene in oncohematology that might affect the functionality of the protein. In this study, the selected mutations were extensively examined by computational screening, and the most deleterious were subjected to a further molecular dynamic simulation in order to uncover the molecular mechanism of the structural damage to the protein altering its biological function. The most significant effect was found for variants I625K, L1047S, and H1170D, presumably affecting the endonuclease activity of DROSHA. Such alterations arisen during MDS progression should be taken into consideration as evoking certain clinical traits in the malignifying clonal evolution.

Highlights

Myelodysplastic syndrome (MDS) refers to a heterogeneous group of closely related clonal hematopoietic disorders commonly found in the aging population
P356Lfs*121 led to the loss of the most important protein features required for the main DROSHA functions: region (490–1374 aa) required for pri-miRNA processing activity and interaction with DGCR8, both RNAse III domains (876–1056 aa and 1107–1233 aa), downstream metal-binding sites, etc
Recent research demonstrated the mutational burden of the DROSHA gene and the common significance of the miRNA processing pathway for MDS emergence [7]; the detailed investigation of DROSHA coding mutations is of primary importance

Summary

Introduction

Myelodysplastic syndrome (MDS) refers to a heterogeneous group of closely related clonal hematopoietic disorders commonly found in the aging population. The downregulated expression of both miRNA processing endonucleases, DICER1 and DROSHA, was demonstrated in MSCs from myelodysplastic syndrome patients compared to normal cells [3]. This observation is accompanied by global miRNA dysregulation and consequent protein expression alteration during MDS progression [4]. A recent analysis of MDS clinical data revealed the high mutational burden in both miRNA processing genes and their association with common MDS mutations [7] Taking these facts together, it can be concluded that the genes of miRNA biogenesis are under mutational pressure during cancer progression, and their disruption can alter cellular proliferation through miRNA regulation. All mutations of this gene found to occur in hematological tissue were studied in detail to provide additional insights into the structural and functional role of DROSHA, and presumably consequent miRNA biogenesis alteration in oncohematology

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Results

Discussion

Conclusion