Fig. 7. A proposed model for two Xrn1-mediated mRNA decay pathways.

a WT cells. Left pathway (red arrows) illustrates the Kis mRNA decay pathway, which begins in the nucleus. Xrn1 binds promoters and stimulates transcription^1–3. During transcription, it binds the emerging transcript⁷³, most probably at its 3’ end^27,. This RNA is protected against Xrn1 activity by a 5’ cap, yet Xrn1 is immediately available upon decapping, or after endonucleolytic RNA cleavage. In this model, we hypothesize that Xrn1 does not dissociate from binding the 3’ end. Thus, upon decapping, Xrn1 binds both the 5’P and the 3’ RNA end (until advance stage of the RNA degradation). This hypothesis remains to be examined experimentally. Following RNA decay, NLS1 is exposed and binds Kap120, and Xrn1 is imported to begin a new cycle. Right pathway (green arrows): the decay of non-Kis mRNAs is, by definition, insensitive to Xrn1 shuttling. It is confined to the cytoplasm and follows the standard model of mRNA decay^8,9. b xrn1^ΔNLS1/2cells. Kis mRNAs are degraded mainly by the Xrn1-independent pathway, quite possibly by the exosome - as it becomes essential in xrn1^ΔNLS1/2 cells (Fig. 5k). In general, we propose that most mRNAs are simultaneously degraded by the two pathways, the impact of each pathway on the overall degradation is mRNA specific and is related to the “Kis value”. See text for more details. Created with “BioRender.com”.