Molecular Cell
Volume 70, Issue 6, 21 June 2018, Pages 1081-1088.e5
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Article
PABP Cooperates with the CCR4-NOT Complex to Promote mRNA Deadenylation and Block Precocious Decay

https://doi.org/10.1016/j.molcel.2018.05.009Get rights and content
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Highlights

  • The human CCR4-NOT complex is a predominant nonspecific deadenylase

  • PAN2/3 trims excessively long tails with minimal impact on mRNA stability

  • CAF1 trims PABPC-free A tails while CCR4 removes PABPC-bound A tails

  • PABPC facilitates mRNA deadenylation while preventing precocious uridylation and decay

Summary

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

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

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These authors contributed equally

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