In a study published in Molecular Cell, a 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, collaborating with Prof. ZHOU Yu from Wuhan University, proposed a novel "degradation-centric" model of RNA sorting, challenging the prevailing view of "export-centric."

In eukaryotes, RNA polymerase II transcribes various types of RNA, which have vastly different fates: some are efficiently exported, while others are rapidly recognized and degraded within the nucleus. An "export-centric" hypothesis has been suggested for nuclear RNA sorting where the export and degradation pathways compete and RNAs that cannot be efficiently exported are subjected to degradation. However, this sorting mechanism may not effectively guarantee the rapid clearance of aberrant RNAs, potentially impacting cellular function.

The exosome is one of the main RNA degradation machines in the cell. It requires the association with multiple cofactors to recognize its wide range of substrates and achieve full activity. The PAXT complex is a key co-factor of the exosome, consisting of the MTR4-ZFC3H1 core and the transient components. PAXT has been suggested to mainly bind to the 3′ region of polyadenylated RNAs, and recruit the exosome via MTR4. The structural similarity of PAXT substrate RNAs to functional mRNAs makes this RNA sorting process particularly challenging.

In this study, researchers unexpectedly discovered that ZFC3H1 binds to the first exons and introns of pre-RNAs early in transcription. 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, researchers comprehensively characterized 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 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 reveals 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, 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.