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Nuclear Export of mRNA

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For protein synthesis, the mature mRNA needs to be transported from the nucleus to the cytoplasm.

Embedded throughout the nuclear membrane are large protein complexes known as nuclear pore complexes or NPCs. These function as selective channels between the nucleus and cytoplasm, only allowing some macromolecules to pass through.

An NPC has a hollow, cylindrical structure composed of a class of proteins called nucleoporins, which has about 30 distinct members.

To pass through the NPC, the mRNA associates with another protein called a nuclear transport receptor. They form an RNA- receptor complex that can now be shuttled through the NPC channel into the cytoplasm, followed by dissociation of the complex.

Now, the receptor can return to the nucleus to transport another mRNA.

The mature mRNAs are a small fraction of the RNA species present in a cell. The remainder consists of junk RNAs, such as pre-spliced mRNA, excised introns, and incompletely or irregularly spliced products.

During transcription and post-transcriptional processing, a regular mRNA with a 5’ cap and a 3’ poly A tail, associates with various proteins such as-Cap binding complex or CBC, Exon junction complex or EJC, PolyA binding proteins, heterogenous nuclear ribonuclear proteins or hnRNPs, and SR proteins.

On the other hand, junk RNAs cannot bind to these proteins and remain stalled.

By detecting the proteins associated with the RNA, the cell distinguishes between correctly processed mRNA and the rest. The junk RNAs are degraded by the nuclear RNA exosome complex.

The eukaryotic nuclear RNA exosome is a RNA-protein complex comprised of a barrel-shaped core through which an RNA molecule is threaded to reach an exonuclease. This enzyme degrades the RNA to nucleotides that are returned to the cellular pool.

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Before mRNAs are exported to the cytoplasm, it is crucial to check each mRNA for structural and functional integrity. Eukaryotic cells use several different mechanisms, collectively known as mRNA surveillance, to look for irregularities in mRNAs. Irregular or aberrant mRNA are rapidly degraded by various enzymes. If a defective mRNA escapes the surveillance, it would be translated into a protein which would either be non-functional or not function properly. One of the primary irregularities in mRNA is the presence of a premature stop codon. This is the result of sequence mutations that code for a Stop Codon prematurely in the reading frame. An estimated 30% of inherited genetic disorders in humans result from these mutations. These mRNAs are degraded in a pathway known as nonsense-mediated decay (NMD). NMD differs from other decay pathways by rapidly degrading mRNAs using 3′→5′ exonucleases.

Another prevalent decay mechanism detects lack of post-transcriptional modifications in mRNAs. RNA polymerase II transcripts are cotranscriptionally modified with a 5’ methylated G cap, and most of them have a chain of Adenine residues at the 3' end. Lack of either or both of these features, targets the mRNA for 5′→3′ exonucleolytic decay.

Other aberrations might be introduced if the mRNA has a single nucleotide mutation. Although this type of irregularity is most frequently observed in tRNAs, mRNAs can also be modified in the presence of reactive oxygen species (ROS), UV light, and alkylating agents. Chemical modifications caused by these agents are detected by NMD, non-stop decay (NSD) and no-go decay (NGD) pathways. All these pathways use specialized proteins that are sensitive to oxidative damage. These proteins recognize oxidized bases and direct the modified mRNAs to degradation pathways that use nucleases to digest the mRNAs.

While the degradation pathways discussed here target irregular mRNAs, they also down-regulate normal cellular mRNAs when they do not need to be translated. This process, formally classified as mRNA turnover, is also important to maintain optimum levels of mRNA in the cellular pool.

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