Nuclear export is a limiting factor in eukaryotic mRNA metabolism.

Autor: Müller, Jason M., Moos, Katharina, Baar, Till, Maier, Kerstin C., Zumer, Kristina, Tresch, Achim
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Zdroj: PLoS Computational Biology; 5/16/2024, Vol. 20 Issue 5, p1-23, 23p
Abstrakt: The eukaryotic mRNA life cycle includes transcription, nuclear mRNA export and degradation. To quantify all these processes simultaneously, we perform thiol-linked alkylation after metabolic labeling of RNA with 4-thiouridine (4sU), followed by sequencing of RNA (SLAM-seq) in the nuclear and cytosolic compartments of human cancer cells. We develop a model that reliably quantifies mRNA-specific synthesis, nuclear export, and nuclear and cytosolic degradation rates on a genome-wide scale. We find that nuclear degradation of polyadenylated mRNA is negligible and nuclear mRNA export is slow, while cytosolic mRNA degradation is comparatively fast. Consequently, an mRNA molecule generally spends most of its life in the nucleus. We also observe large differences in the nuclear export rates of different 3'UTR transcript isoforms. Furthermore, we identify genes whose expression is abruptly induced upon metabolic labeling. These transcripts are exported substantially faster than average mRNAs, suggesting the existence of alternative export pathways. Our results highlight nuclear mRNA export as a limiting factor in mRNA metabolism and gene regulation. Author summary: In our work, we aim to quantify two fundamental processes in the life cycle of a eukaryotic messenger RNA (mRNA), namely export from the nuclear compartment to the cytosol, and degradation. To enable a genome-wide evaluation, we have implemented an experimental-bioinformatics approach. We use a chemical moiety, 4-thiouridine (4sU), which is incorporated into RNA molecules when added to the solution, to mark RNA which is recently synthesized and distinguish it from already existing RNA. We take a time series of recent and already existing RNA within both the nuclear and cytoplasmic cellular compartments. We have devised a computational model that can reliably quantify mRNA nuclear export and cytosolic degradation rates from this data. We revealed that the export of mRNA from the nucleus to the cytoplasm emerges as a comparatively tardy event. Subsequently, mRNA molecules within the cytoplasm experience swift degradation. This identifies the nucleus as the predominant residence for the greater portion of an mRNA's lifecycle. Yet, we have also found notable exceptions from this scheme which are immediately exported after transcription without delay, suggesting the plausible existence of alternative mRNA export pathways. In sum, our research underscores the pivotal role of nuclear mRNA export as a determining factor in the orchestration of mRNA metabolism and the regulation of gene expression within eukaryotic cells. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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