Molecular mechanism of mutations in Microprocessor causing Wilms tumors [mRNA]

ABSTRACT: The Microprocessor complex, consisting of DROSHA and DGCR8, is essential for miRNA maturation and plays a critical role in gene regulation. Mutations in this complex's components are frequently associated with Wilms tumor (WiT), a common pediatric kidney cancer. Understanding the functional impacts of these mutations is key to elucidating WiT pathogenesis. To this end, we developed an innovative Microsensor system to dynamically evaluate Microprocessor function in human cellular environments. Using this tool, we introduced and analyzed the DGCR8-E518K mutation, previously identified in WiT patients. This mutation was shown to significantly disrupt cellular homeostasis, affecting proliferation, apoptosis, and migration. On a molecular level, we demonstrated that the E518K mutation impairs the Microprocessor's efficiency in processing a specific subset of pri-miRNAs that lack the canonical 16-20 nucleotide mismatch feature, leading to abnormal miRNA expression profiles. Additionally, cells expressing the E518K mutant exhibited increased susceptibility to ferroptosis, as indicated by heightened sensitivity to the pro-ferroptotic agent RSL3. Our findings provide new insights into the Microprocessor's role in WiT, with the Microsensor system offering a robust platform for exploring the molecular mechanisms of Microprocessor-associated mutations. This study lays the groundwork for future in vivo research and the potential development of therapeutic strategies targeting the Microprocessor pathway in WiT.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276798 | GEO | 2025/03/10

REPOSITORIES: GEO