PABP Cooperates with the CCR4-NOT Complex to Promote mRNA Deadenylation and Block Precocious Decay

Mol Cell. 2018 Jun 21;70(6):1081-1088.e5. doi: 10.1016/j.molcel.2018.05.009.

Abstract

Multiple deadenylases are known in vertebrates, the PAN2-PAN3 (PAN2/3) and CCR4-NOT (CNOT) complexes, and PARN, yet their differential functions remain ambiguous. Moreover, the role of poly(A) binding protein (PABP) is obscure, limiting our understanding of the deadenylation mechanism. Here, we show that CNOT serves as a predominant nonspecific deadenylase for cytoplasmic poly(A)+ RNAs, and PABP promotes deadenylation while preventing premature uridylation and decay. PAN2/3 selectively trims long tails (>∼150 nt) with minimal effect on transcriptome, whereas PARN does not affect mRNA deadenylation. CAF1 and CCR4, catalytic subunits of CNOT, display distinct activities: CAF1 trims naked poly(A) segments and is blocked by PABPC, whereas CCR4 is activated by PABPC to shorten PABPC-protected sequences. Concerted actions of CAF1 and CCR4 delineate the ∼27 nt periodic PABPC footprints along shortening tail. Our study unveils distinct functions of deadenylases and PABPC, re-drawing the view on mRNA deadenylation and regulation.

Keywords: CAF1; CCR4; CCR4-NOT; PABPC; PAN2-PAN3; PARN; RNA decay; deadenylation; poly(A) tail; uridylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Line / metabolism
  • Cytoplasm / metabolism
  • Exoribonucleases / genetics
  • Exoribonucleases / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism*
  • Poly A / metabolism
  • Poly(A)-Binding Proteins / genetics
  • Poly(A)-Binding Proteins / metabolism*
  • Polyadenylation
  • RNA Stability*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • Receptors, CCR4 / genetics
  • Receptors, CCR4 / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptome

Substances

  • CCR4 protein, human
  • Carrier Proteins
  • NR4A2 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • PAN3 protein, human
  • Poly(A)-Binding Proteins
  • RNA, Messenger
  • Receptors, CCR4
  • Transcription Factors
  • Poly A
  • Exoribonucleases
  • PAN2 protein, human