The transfer and expression of genetic information form the material basis of all life activities. In eukaryotes, RNA polymerase II transcribes various types of RNA, which, despite their high structural similarity, have vastly different fates: some are efficiently exported, while others are rapidly recognized and degraded within the nucleus. The correct sorting of RNA into either the export or degradation pathway is a crucial step in ensuring the accurate expression of genetic information.
Recent studies suggest an export-centric hypothesis for nuclear RNA sorting, where the export and degradation pathways compete and RNAs that cannot be efficiently exported are subjected to degradation. However, this export-centric RNA sorting mechanism may not effectively guarantee the rapid clearance of aberrant RNAs, potentially impacting cellular function.
In a study published in Mol Cell, a research team led by Prof. CHENG Hong from the Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences, in collaboration with Prof. ZHOU Yu from Wuhan University proposed a novel "degradation-centric" model of RNA sorting, challenging the prevailing view of "export- centric" in RNA sorting.
The exosome is one of the main RNA degradation machines in the cell, involved in the fate regulation of nearly every RNA molecule. To recognize its wide range of substrates and achieve full activity, the exosome requires the association with multiple cofactors. The PAXT complex (PolyA eXosome Targeting connection) is a key co-factor of the exosome, consisting of the MTR4-ZFC3H1 core and the transient components, such as PABPN1, ZC3H3, and RBM26/27. Previous studies have suggested that PAXT mainly binds to the 3′ region of polyadenylated RNAs, and recruits the exosome via MTR4. The structural similarity of PAXT substrate RNAs to functional mRNAs makes this RNA sorting process particularly challenging.
In this study, the researchers unexpectedly discovered that ZFC3H1 binds to the first exons and introns of pre-RNAs early in transcription. Interestingly, during this phase, ZFC3H1 adopts a self-closed conformation that obstructs MTR4 from recruiting the exosome, thereby preventing RNA degradation.This "occupancy" mode effectively prevents premature recruitment of export factors, avoiding export dysregulation.
Through multi-omics analyses, the study comprehensively characterizes the features of PAXT degradation substrate RNAs, including fewer exons, shorter lengths, and longer polyA tails. During co-transcriptional splicing, ZFC3H1 is outcompeted by export factors on multi-exonic RNAs. Conversely, on short RNAs with fewer exons, PAXT components (such as ZC3H3 and RBM26/27) are preferentially recruited to the 3′ end via the elongated polyA tail, triggering the opening of ZFC3H1 and initiating exosomal degradation.
In summary, this study delineates how RNA fate is preset at the early stage of transcription and reshaped at the following stages to confer the best selectivity in sorting mature RNAs into the export or degradation pathway. Based on this discovery, the researchers propose a degradation-centric nuclear RNA sorting model that ensures both the rapid decay of unwanted RNAs and the efficient export of functional mRNAs.
Reference: https://doi.org/10.1016/j.molcel.2024.09.032
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