H2020Индивидуална стипендия2022–2024

UPFs_NMD · Up-frameshift protein interactions in translation termination and nonsense-mediated mRNA decay

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2022-03-01 → 2024-02-29
Финансиране от ЕС: 212 934 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Взаимодействията между протеините, които разпознават грешки в генетичните инструкции (mRNA), се анализират чрез техните молекулярни структури. Разбирането на този механизъм помага при разработването на стратегии за лечение на генетични заболявания като кистична фиброза и мускулна дистрофия.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Up-frameshift protein interactions in translation termination and nonsense-mediated mRNA decay

The genetic code is often compared to a "blueprint" because it holds the essential instructions for a cell's survival. Think of DNA like a book - but how does the cell actually "read" it? The instructions stored within DNA are "read" in two steps: transcription and translation. Transcription is the first step in gene expression, Transcription is like making a copy of a specific page in the book. This copy, called messenger RNA (mRNA) is needed to make a protein. This translation happens with the help of machines called ribosomes. Nonsense-mediated mRNA decay (NMD) is a quality control system found in all eukaryotic cells. Its job is to spot specific errors namely translation stop signals in the mRNA - like typos in a text - and get rid of the mRNA. This prevents the cell from making incomplete or harmful proteins. NMD proteins get activated when the ribosome encounters a stop sign at an inappropriate position in the mRNA. This area of research is highly important for both medicine and society because NMD plays a key role in numerous human genetic diseases like β-thalassemia, cystic fibrosis, Becker muscular dystrophy, and Duchenne muscular dystrophy. Furthermore, disruption of NMD can lead to neurodevelopmental disorders, immune diseases, and cancer. Understanding how NMD works is crucial for developing new treatment strategies. To that end, there are still big questions to answer, including how NMD proteins recognize substrates and become activated. This project had several primary goals. I studied the interactions among NMD proteins to better understand their molecular function. Secondly, I carried out structural investigations to visualize these interactions of NMD components. The MSCA Individual Fellowship had the parallel aims of advancing my personal and professional development and undertaking outreach initiatives such as public engagement and dissemination of findings – this project was ideally suited for me to learn new practical skills, gain leadership experience, and engage in outreach activities.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

In eukaryotes, gene expression is highly regulated involving multistep pathways in which mRNA plays a crucial role. Cells have evolved surveillance mechanisms able to detect and degrade defective transcripts. Nonsense-mediated mRNA decay (NMD) is a mRNA surveillance mechanism which detects faulty mRNAs with premature termination codons (PTCs) and targets these transcripts to decay. By modulating the expression of physiological mRNAs, NMD acts as a post-transcriptional regulator controlling important cellular processes in development, stress response, immunity and neuronal differentiation. NMD is of medical importance because mutations or copy number variations of the NMD factors are implicated in human neurological disorders, intellectual disability, schizophrenia, autism, immune diseases and cancer. The mammalian NMD machinery comprises the proteins UPF1, UPF2, and UPF3B, eukaryotic release factors (eRF1 and eRF3a), SMG1 kinase and SMG5-9. Recently UPF3B was found to have a role in translation termination at a premature stop codon, interacting directly with the ribosome, release factors and UPF1, requiring modification of prevalent NMD models. To understand the molecular mechanisms of UPF3B and its role in NMD, this proposal aims to determine the molecular architecture of UPF3B in complex with UPF1, ribosome and mRNA. Furthermore, I will explore the role of the helicase and ubiquitin ligase activities of UPF1 in NMD and protein decay. I will use biochemistry, biophysics, X-ray crystallography and cryo-electron microscopy to identify the UPF3B domains involved in the recognition of NMD substrates and to investigate how UPF3B binding to the UPF1-RNA complex helps trigger mRNA decay. Such information will shed light on how translation termination and assembly of the NMD machinery are coordinated and therefore will be of key importance for the future development of therapeutic approaches for the future development of therapeutic approaches for NMD- related diseases.

Оригинален текст от CORDIS (на английски).

Участници

UNIVERSITY OF BRISTOL · BRISTOLКоординаторОбединеното кралство