MOD-PROT · The role of tRNA processing and modifications in protein quality control.
„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“
- Период
- 2018-09-01 → 2020-08-31
- Финансиране от ЕС
- 159 461 €
- Участници
- 2
- Схема
- MSCA-IF-EF-ST
Линиите свързват координатора с партньорите.
Накратко на български
Химичните модификации на транспортните РНК (tRNA), като например работата на ензима Mod5, влияят върху скоростта на синтез на протеините. Разбирането на този процес помага да се разбере как клетките поддържат качеството на протеините и предотвратяват тяхното неправилно натрупване.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
The role of tRNA processing and modifications in protein quality control.
Life is possible because cells have the inherent capacity to translate their genetic information into functional proteins. This process is called translation and within this complex and tightly regulated process, transfer RNAs (tRNAs) take a fundamental role by bringing the correct amino acid to the growing nascent peptide. tRNAs are highly modified molecules because they undergo several posttranscriptional chemical modifications. However, the relevance of many of those chemical modifications in tRNA maturation and, more importantly, during translation remains to be understood. Previously, the host group discovered that cells lacking certain tRNA modifications in the anticodon induce translational slow down, a defect that triggers widespread protein aggregation in yeast and nematodes. This was the first evidence linking tRNA metabolism to protein quality control and established tRNA metabolism as a novel layer in the regulation of protein homeostasis. This project aimed to explore the relationship between tRNA modifications and protein homeostasis (proteostasis). Our objective was to investigate whether modifications in the whole tRNA body (i.e. in addition to the anticodon) hampered translation speed and, if yes, how did it effect the cell’s proteostasis. We focused on Mod5, a transfer RNA (tRNA) modifying enzyme required for the N6-isopentenylation of adenosine (i6A) at position 37 of cytoplasmatic and mitochondrial tRNATyr, tRNACys and tRNASer in bacteria, yeast, nematodes and humans. We found that yeast cells lacking this gene display codon-specific slow down at codons UCG (Ser), UAU (Tyr) and UGU (Cys). Transcriptomic and translatomic data revealed that the loss of the i6A modification increases mitochondrial translation while cytoplasmatic translation is decreased. Moreover, yeast mutants display a mild impairment of respiratory capacity. Finally, we found that MOD5 synthetically interacts with the mitochondrial ribosome quality control. The project has been delayed by three months due to the Covid-19 related shutdown in Switzerland.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Translation of the genetic code into functional proteins is a fundamental biological process essential for cell survival and function. tRNAs are critical in this process because they recognize the codons on the messenger RNA and bring the cognate amino acid to the nascent peptide. To become functional, tRNAs undergo a series of processing steps and chemical modifications. Recently, my host group discovered that cells lacking wobble uridine modifications in the tRNA anticodon display translational slow down, a defect that triggers widespread protein aggregation in yeast and nematodes. These findings were the first to link tRNA metabolism to protein quality control and established tRNA metabolism as a novel layer in the regulation of protein homeostasis. However, the mechanisms underlying this phenomenon remain unknown.My goal is to elucidate how tRNA processing and modifications regulate protein quality control, by integrating genetic, biochemical, transcriptomic, translatomic and proteomic approaches.- First, I will identify tRNA biosynthesis genes that are critical for protein aggregation, by assessing global protein homeostasis in yeast cells lacking genes required for tRNA processing and modifications. - Second, I will characterize transcriptome-wide translation by ribosome profiling to determine whether protein aggregation phenotypes are accompanied by translational defect. This will reveal which tRNA processing and modifications are essential for optimal co-translational protein folding. - Finally, I will use yeast and nematode models of neurodegenerative diseases to test the functional importance of candidate steps of tRNA metabolism in disease-associated protein aggregation.My project will comprehensively address the link between tRNA metabolism and protein homeostasis. In particular, it will bridge RNA and protein quality control pathways and shed mechanistic insights into neurodegenerative diseases that originate from tRNA dysfunction.
Оригинален текст от CORDIS (на английски).
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Данни: CORDIS, © Европейски съюз