5'-3' exoribonuclease 1 (XRN1) (XRN1)

5'-3' exoribonuclease 1 (XRN1) is a highly conserved enzyme that serves as the primary driver of cytoplasmic mRNA decay in eukaryotic cells. It processively degrades 5'-monophosphorylated RNA transcripts following their decapping, a process that occurs within specialized cytoplasmic aggregates known as processing bodies (P-bodies). Beyond its fundamental role in maintaining RNA homeostasis, XRN1 acts as a critical regulator of the innate immune system by preventing the accumulation of endogenous double-stranded RNA (dsRNA) and other aberrant RNA species. When XRN1 activity is lost or inhibited, these RNA species accumulate and trigger the MDA5 and PKR sensing pathways, inducing a robust Type I interferon response and subsequent apoptosis. This mechanism has positioned XRN1 as a promising therapeutic target in oncology, particularly for 'TISG-high' tumors (those with an intrinsically high interferon-stimulated gene signature) which exhibit selective vulnerability to XRN1 inhibition. Additionally, XRN1 is involved in the life cycles of numerous viruses, such as Hepatitis C and various Flaviviruses, where it can function as either a restriction factor or a co-opted host factor required for viral RNA processing. Current drug development efforts, such as those by Accent Therapeutics, are focused on small-molecule allosteric inhibitors of XRN1 to treat cancer and potentially enhance the stability of therapeutic mRNA drugs.

Other names

SEP1Strand-exchange protein 1 homolog5'-3' exoribonuclease 1Xrn1

XRN1 is targeted by small-molecule allosteric inhibitors that block its exoribonuclease activity, leading to the accumulation of double-stranded RNA and activation of innate immune pathways. It is also regulated by microRNAs like miR-204, which bind to the XRN1 mRNA transcript to repress translation and induce degradation.