AGOras · ARGONAUTE proteins transport routes and subcelular activities
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-09-01 → 2023-08-31
- EU contribution
- €160,932
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
ARGONAUTE proteins transport routes and subcelular activities
Small RNAs are essential during development, stress responses, to preserve genome integrity and for general immunity to viruses. In humans, over 60% of the genes are regulated by small RNA. Deregulation of small RNA pathways are associated with a large number of human diseases, particularly cancer. To fulfill their biological function, all small RNA, are loaded into ARGONAUTE (AGO) proteins, which recognize and negatively regulate the target genes across kingdoms being themselves conserved throughout evolution. Eukaryotic AGO proteins are evolutionarily conserved but depending on the organism and the sRNA pathway involved, AGO proteins have nuclear and/or cytoplasmic localizations. Cytoplasmic AGO-sRNA complexes silence genes post-transcriptionally (PTGS) through RNA target cleavage, translational inhibition, and/or mRNA decay. In the nucleus, AGO proteins act on transcriptional gene silencing (TGS), chromatin modifications, splicing and DNA repair. While these AGO mediated processes are reasonably well understood, the transport routes involved and their regulation, are largely unknown. The overall goal of my project AGOras was to study how this AGO proteins movement could affect small RNAs and gene regulation. To achieve this, I address the following objectives: 1- To identify the signals responsible for AGO proteins subcellular localization 2- To understand how these signals are read by other proteins that move them between subcellular compartments 3- To dissect cytoplasmic and nuclear functions of AGO-sRNA pathways in plants The interest in RNA molecules action goes beyond mere mechanistic knowledge, understanding how small RNA act is of paramount importance since RNA based vaccines or drugs are commercialized on a daily base. The outcome of AGOras will contribute to the generation of small RNA based tools to control gene expression with potential impact in therapeutic, veterinary, and agronomic sectors.
Data: CORDIS, © European Union
Project objective
Small RNAs (sRNA) have emerged as major players in a multitude of pathways, controlling development and preserving genome integrity in plant and animals. To fulfill their biological function, sRNA are loaded into ARGONAUTE (AGO) proteins, together this AGO/sRNA complex recognizes and regulates the target genes. Depending on the organism and the sRNA pathway involved, AGOs have nuclear and/or the cytoplasmic localization and functions. Although globally AGO mediated processes are reasonably understood, the transport routes involved, their shuttling regulation and transient subcellular roles remain completely unknown. This proposal outlines a series of mutually reinforcing experiments to mechanistically study the transport routes and subcellular roles of AGO-sRNA complexes. In details, combining cell biology, RNA biochemistry, protein modeling, bioinformatics, deep-sequencing analyses, nuclear fractionation methods and single-molecule studies the proposed project aims to: 1) Identify key subcellular localization signals of AGO proteins; 2) Decipher AGO shuttling mechanism and their regulation; and 3) Dissect cytoplasmic and nuclear roles of AGO proteins on RNA pathways. The anticipated results will provide a crucial breakthrough in the eukaryotic RNA pathways and gene regulation fields. The interest in non-coding RNA action goes beyond mere mechanistic knowledge. Understanding non-coding RNA action is of paramount importance given the extraordinary potential held by the therapeutic, veterinary and agronomic exploitation of these molecules. As a result, the knowledge on the transport routes and subcellular roles of AGO-sRNA complexes obtained during the proposed project will provide an important contribution to European excellence and competitiveness in the field.
Original text from CORDIS.
Participants
- CENTRE DE RECERCA EN AGRIGENOMICA CSIC-IRTA-UAB-UB · CERDANYOLA DEL VALLESCoordinatorSpain
Links
Data: CORDIS, © European Union