G4-PTROs · Regulatory network of G-quadruplex dependent Post-Transcriptional mRNA Operons (PTROs)
„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“
- Период
- 2016-05-01 → 2018-04-30
- Финансиране от ЕС
- 183 455 €
- Участници
- 1
- Схема
- MSCA-IF-EF-ST
Линиите свързват координатора с партньорите.
Накратко на български
Специални структури в РНК, наречени G-квадруплекси, контролират синтеза на протеини, като например ограничават транслацията в определени части на молекулата. Разбирането на тези механизми и протеините, които взаимодействат с тях, помага за откриването на нови терапевтични цели при рак и неврологични заболявания.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Regulatory network of G-quadruplex dependent Post-Transcriptional mRNA Operons (PTROs)
Understanding post-transcriptional control is crucial to gain detailed knowledge of gene expression. G-quadruplexes (G4s) are important secondary structures in RNAs and represent integral signaling components that modulate post-transcriptional activity of rG4 containing mRNAs. Especially the finding that rG4s are located in mRNAs of several cancer and neurologically relevant genes points towards largely unexplored opportunities to identify new therapeutically avenues. In essence, G4-specific RNA binding proteins are recruited to rG4s and determine the ultimate fate of G4-containing mRNAs. These interactions deserve to be further studied. Therefore, the overall objective of my project was to further shed light on rG4 guided mechanisms and how the functional consequences of protein-rG4 interactions impact mRNA fate. Throughout the two-year duration of this fellowship, I have investigated and utilized different techniques to understand the function of rG4s. I have confirmed that presence of rG4s in 5’UTR restricts translation in cells. In a collaborative effort, we have identified several novel rG4 interacting proteins that represent potential therapeutic targets modulating a defined set of mRNAs in a rG4 dependent manner. Furthermore, I managed to establish a robust reporter system to study rG4 function in 5’UTRs. This reporter system will allow me to identify transient factors that impact the translation of rG4 containing mRNAs. All aspects of this work are currently still ongoing and I am looking forward to finish planned experiments as it is an exciting time to explore rG4 driven mechanisms.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Many studies of global gene expression focus solely on studying the transcriptome thereby only assessing mRNA abundance. However, transcription is only a single layer of gene expression and recently, the influence of post-transcriptional regulation has become undeniable. Rather underrepresented players in post-transcriptional control are G-quadruplexes (G4s). These stable structures can form guanine tetrads in DNA and RNA via p-p-stacking of several planar arrangements of four guanine bases stabilized by Hoogsteen hydrogen bonds and a central metal cation. Recent reports have pointed to an important regulatory role of G4 motives in key cellular functions including pre-mRNA processing, RNA turnover, mRNA transport thereby suggesting intriguing links to human diseases as cancer and neurological disorders. G4 structures in mRNAs seem to act as signaling components that constitute an own post-transcriptional operon. Recruitment of G4-specific RBPs then determines the ultimate fate of G4-containing mRNAs. Not many RBPs or upstream regulatory factors of G4s have been identified and the functional consequences of these interactions are not known. In this proposal I will address these questions. First, I will identify mRNAs that are differentially translated and/or stabilized in the presence of the G4 specific ligand pyridostatin (PDS), which stabilizes G4 structures. The resulting comprehensive list of mRNAs will be the first data set that provides a mechanistically link of G4 motive regulation. Secondly, I will identify factors in the G4 regulatory network using a genome wide shRNA assay to determine proteins that modulate the stability and/or the translation of G4 motive containing mRNAs. It is important to understand G4 structure-function relationships and upstream regulatory processes as the emerging link between G4 formation and human disease opens up an exciting research direction that has potential implications for therapeutic intervention.
Оригинален текст от CORDIS (на английски).
Участници
- THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE · CAMBRIDGEКоординаторОбединеното кралство
Връзки
Данни: CORDIS, © Европейски съюз