Summary
Cell tightly regulate mRNA processing, localisation and stability to ensure accurate gene expression in diverse cellular states and conditions. Most of these mRNA regulation steps have traditionally been thought to primarily happen before translation. However, recent discoveries highlight the role of nascent polypeptides on translating ribosomes in the active regulation of mRNAs. As the nascent protein emerges from the ribosome, it marks the identity of the encoding mRNA by its unique amino acid sequence. This allows cotranslational engagement by specific polypeptide recognition factors on the ribosome, providing them access to the associated mRNA. A striking example for such regulation is the negative feedback loop in the expression of tubulins known as “tubulin autoregulation”. In this case, tubulin mRNA is degraded cotranslationally when cells sense excess free tubulin, which is critical during mitosis to ensure faithful chromosome segregation. Recently, the first specific factor in this pathway has been identified: TTC5 recognises the N-terminus of nascent tubulin emerging from the translating ribosome and triggers degradation of the associated mRNA. However, the events leading to tubulin mRNA decay downstream of TTC5 remain elusive.
In mRNA-DEG-RIBOSOME I will use tubulin autoregulation as a model system to study how the nascent chain on translating ribosomes directs mRNA degradation. Specifically, I aim to: (1) identify factors acting downstream of TTC5 required for tubulin mRNA degradation using cutting-edge mass spectrometry and genetic screening methods; (2) understand the mechanistic role of each factor in TTC5-directed mRNA degradation by using a powerful in vitro reconstitution approach; and (3) expand the understanding of nascent chain-dependent mRNA degradation by investigating related feedback systems. Thus, my work will to provide a conceptual framework for how cells have evolved to exploit nascent polypeptide recognition to direct mRNA fate.
In mRNA-DEG-RIBOSOME I will use tubulin autoregulation as a model system to study how the nascent chain on translating ribosomes directs mRNA degradation. Specifically, I aim to: (1) identify factors acting downstream of TTC5 required for tubulin mRNA degradation using cutting-edge mass spectrometry and genetic screening methods; (2) understand the mechanistic role of each factor in TTC5-directed mRNA degradation by using a powerful in vitro reconstitution approach; and (3) expand the understanding of nascent chain-dependent mRNA degradation by investigating related feedback systems. Thus, my work will to provide a conceptual framework for how cells have evolved to exploit nascent polypeptide recognition to direct mRNA fate.
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More information & hyperlinks
| Web resources: | https://cordis.europa.eu/project/id/101029853 |
| Start date: | 01-10-2021 |
| End date: | 30-09-2023 |
| Total budget - Public funding: | 212 933,76 Euro - 212 933,00 Euro |
Cordis data
Original description
Cell tightly regulate mRNA processing, localisation and stability to ensure accurate gene expression in diverse cellular states and conditions. Most of these mRNA regulation steps have traditionally been thought to primarily happen before translation. However, recent discoveries highlight the role of nascent polypeptides on translating ribosomes in the active regulation of mRNAs. As the nascent protein emerges from the ribosome, it marks the identity of the encoding mRNA by its unique amino acid sequence. This allows cotranslational engagement by specific polypeptide recognition factors on the ribosome, providing them access to the associated mRNA. A striking example for such regulation is the negative feedback loop in the expression of tubulins known as “tubulin autoregulation”. In this case, tubulin mRNA is degraded cotranslationally when cells sense excess free tubulin, which is critical during mitosis to ensure faithful chromosome segregation. Recently, the first specific factor in this pathway has been identified: TTC5 recognises the N-terminus of nascent tubulin emerging from the translating ribosome and triggers degradation of the associated mRNA. However, the events leading to tubulin mRNA decay downstream of TTC5 remain elusive.In mRNA-DEG-RIBOSOME I will use tubulin autoregulation as a model system to study how the nascent chain on translating ribosomes directs mRNA degradation. Specifically, I aim to: (1) identify factors acting downstream of TTC5 required for tubulin mRNA degradation using cutting-edge mass spectrometry and genetic screening methods; (2) understand the mechanistic role of each factor in TTC5-directed mRNA degradation by using a powerful in vitro reconstitution approach; and (3) expand the understanding of nascent chain-dependent mRNA degradation by investigating related feedback systems. Thus, my work will to provide a conceptual framework for how cells have evolved to exploit nascent polypeptide recognition to direct mRNA fate.
Status
CLOSEDCall topic
MSCA-IF-2020Update Date
28-04-2024
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