H2020Индивидуална стипендия2022–2023

RNA Smuggling · Mechanistic analysis of piRNA precursor nuclear export

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

Период: 2022-01-01 → 2023-12-31
Финансиране от ЕС: 174 167 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Механизмите за изнасяне на предхождащите piRNA молекули от ядрото в цитоплазмата при плодовите мухи се анализират в детайли. Разбирането на този процес помага да се разбере как се поддържа цялостта на генома в половите клетки.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Mechanistic analysis of piRNA precursor nuclear export

The export of messenger RNA (mRNA) from the nucleus to the cytoplasm is a key step in eukaryotic gene expression. mRNAs are transcribed by RNA Polymerase II as pre-mRNAs, which subsequently undergo a series of processing steps such as capping, splicing and poly-adenylation to generate a mature mRNA. Each of these processing steps is accompanied by the deposition of proteins on the mRNA, serving as ‘processing marks’, leading to the establishment of nuclear ribonucleoprotein complexes (mRNPs). To discriminate mature mRNPs form pre-mRNAs and other RNAs in the nucleus these processing marks must be recognized by the mRNA export machinery Despite the fact that key components of mRNA export have been discovered in genetic screen over two decades ago we still lack a mechanistic understanding of this essential process. piRNAs are 23-30nt short RNAs which are key for the silencing of transposable elements, and thus for the maintenance of genome integrity in the germline. piRNAs are processed from a long precursor transcript in the cytoplasm. Unlike mRNAs, this precursor does not undergo processing in the nucleus and thus lacks key features of mRNPs. However, the precursor has to be exported to the cytoplasm to to evade nuclear degradation and to allow for the generation of piRNAs. Interestingly, previous research had uncovered a piRNA precursor export pathway in the Drosophila germline that hijacks key mRNA export components, namely the THO complex and the DExD ATPase Uap56, and combines them with pathway specific factors, such as Bootlegger and Nxf3, a homolog of the mRNA export factor Nxf1. Here I aimed at dissecting the export of piRNA precursor transcripts in mechanistic detail. Understanding this specialized pathway held promise to gain new insights into the function of enigmatic mRNA export factors, such as the THO complex and UAP56, thus generating an entry point for the study of mRNA export. This approach turned out to be fruitful and I could uncover a mechanistic model for the nuclear export of messenger RNA, presumably conserved in all eukaryotes from yeast to human.

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

Цел на проекта

Nuclear export of newly synthesized RNA to the cytoplasm is an essential step in eukaryotic gene expression, yet the participating proteins and their interplay remain poorly understood at the molecular level. Here, I propose to study RNA export of a family of long non-coding RNAs to elucidate fundamental principles underlying the regulated assembly of export-competent RNPs. I will focus on the precursors of piRNAs, a class of small regulatory RNAs. These transcripts are generated by RNA Polymerase II from heterochromatic, transposon-rich loci and are processed into piRNAs in the cytoplasm to specify transposon silencing. Notably, piRNA precursors violate mRNA quality control hallmarks and thus have to bypass degradation in the nucleus for their export. For this a specialized pathway evolved, combining canonical mRNA export factors with novel or neo-functionalized components. I propose a holistic approach combining quantitative biochemistry, structural biology and genetics to integrate known and novel components into a coherent model of piRNA-precursor export. I aim at understanding (1) the recruitment of export factors to sites of transcription, and (2) the nature and regulation of a nuclear piRNP complex consisting of piRNA factors and the canonical mRNA export components UAP56 and THO complex. The molecular function and regulation of these highly conserved proteins is poorly understood. Elucidating how piRNA-precursor export hijacks canonical RNA export factors to avoid mRNA quality control thus holds great promise to uncover general principles of RNA cargo loading onto NXF family proteins and the molecular principles of nuclear RNA export.

Оригинален текст от CORDIS (на английски).

Участници

INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH · WienКоординаторАвстрия