Overview
Doctoral study program: Life Sciences (Faculty of Science, Masaryk University)
Supervisor: Richard Štefl
Annotation
This PhD theme focuses on unraveling the intricate process of Argonaute protein loading by small RNAs, acritical step in gene regulation within RNA-silencing pathways, which are pivotal in both healthy and diseasedstates of animals and plants. Despite over two decades of research into the microRNA pathway and RNAinterference, the precise mechanisms of miRNA strand selection and transfer to Argonaute proteins remainelusive. We propose the existence of two distinct mammalian Argonaute loading pathways, orchestrated byDicer and heat shock protein chaperones, which both involve charged intrinsically disordered regions thathave been overlooked in previous structural studies. The PhD project aims to dissect these mechanismsusing electron cryomicroscopy (cryoEM). The objective is to elucidate the structures of critical complexesinvolving heat shock protein chaperone/co-chaperone-Argonaute-RNA and Dicer-Argonaute-RNAassemblies. By integrating cryoEM with functional analyses, the project aspires to establish the mechanisticprinciples of Argonaute loading. The findings of this PhD project will be instrumental in advancing RNAbasedtherapeutic applications and understanding one of the most crucial regulatory cellular processes.
Recommended literature
- Dicer structure and function: conserved and evolving features. Zapletal D, Kubicek, K, Svoboda P, Stefl R EMBO Reports (2023) 24:e57215 doi:10.15252/embr.202357215
- microRNAs in action: biogenesis, function and regulation. Shang R, Lee S, Senavirathne G, Lai EC. Nat Rev Genet. 2023 doi:10.1038/s41576-023-00611-y.
Requirements for candidate
Biochemistry/molecular biology
More information: RG Structural Biology of Gene Regulation
Information about the application process: https://www.ceitec.eu/ls-mm-phd/
Application webpage: https://www.ceitec.eu/deciphering-the-argonaute-loading-mechanisms-in-rna-silencing-pathways/t11456
