A low-complexity region in human XRN1 directly recruits deadenylation and decapping factors in 5'-3' messenger RNA decay

Nucleic Acids Res. 2019 Sep 26;47(17):9282-9295. doi: 10.1093/nar/gkz633.


XRN1 is the major cytoplasmic exoribonuclease in eukaryotes, which degrades deadenylated and decapped mRNAs in the last step of the 5'-3' mRNA decay pathway. Metazoan XRN1 interacts with decapping factors coupling the final stages of decay. Here, we reveal a direct interaction between XRN1 and the CCR4-NOT deadenylase complex mediated by a low-complexity region in XRN1, which we term the 'C-terminal interacting region' or CIR. The CIR represses reporter mRNA deadenylation in human cells when overexpressed and inhibits CCR4-NOT and isolated CAF1 deadenylase activity in vitro. Through complementation studies in an XRN1-null cell line, we dissect the specific contributions of XRN1 domains and regions toward decay of an mRNA reporter. We observe that XRN1 binding to the decapping activator EDC4 counteracts the dominant negative effect of CIR overexpression on decay. Another decapping activator PatL1 directly interacts with CIR and alleviates the CIR-mediated inhibition of CCR4-NOT activity in vitro. Ribosome profiling revealed that XRN1 loss impacts not only on mRNA levels but also on the translational efficiency of many cellular transcripts likely as a consequence of incomplete decay. Our findings reveal an additional layer of direct interactions in a tightly integrated network of factors mediating deadenylation, decapping and 5'-3' exonucleolytic decay.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA-Binding Proteins / genetics*
  • Endoribonucleases / genetics
  • Exoribonucleases / genetics*
  • Humans
  • Microtubule-Associated Proteins / genetics*
  • Multiprotein Complexes / genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / genetics
  • Proteins / genetics
  • RNA Caps / genetics*
  • RNA Stability / genetics*
  • RNA, Messenger / chemistry
  • RNA, Messenger / genetics
  • Receptors, CCR4 / genetics
  • Repressor Proteins / genetics
  • Trans-Activators / genetics
  • Transcription Factors / genetics


  • CCR4 protein, human
  • CIR1 protein, human
  • CNOT8 protein, human
  • DNA-Binding Proteins
  • EDC4 protein, human
  • Microtubule-Associated Proteins
  • Multiprotein Complexes
  • NR4A2 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • PATL1 protein, human
  • Proteins
  • RNA Caps
  • RNA, Messenger
  • Receptors, CCR4
  • Repressor Proteins
  • Trans-Activators
  • Transcription Factors
  • mRNA decapping enzymes
  • Endoribonucleases
  • Exoribonucleases
  • XRN1 protein, human
  • DCP1A protein, human