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

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...

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Bibliographic Details
Published in:Molecular cell 2018-06, Vol.70 (6), p.1081-1088.e5
Main Authors: Yi, Hyerim, Park, Joha, Ha, Minju, Lim, Jaechul, Chang, Hyeshik, Kim, V. Narry
Format: Article
Language:English
Subjects:
CAF1
Carrier Proteins - genetics
Carrier Proteins - metabolism
CCR4
CCR4-NOT
Cell Line - metabolism
Cytoplasm - metabolism
deadenylation
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
PABPC
PAN2-PAN3
PARN
Poly A - metabolism
poly(A) tail
Poly(A)-Binding Proteins - genetics
Poly(A)-Binding Proteins - metabolism
Polyadenylation
Receptors, CCR4 - genetics
Receptors, CCR4 - metabolism
RNA decay
RNA Stability
RNA, Messenger - genetics
RNA, Messenger - metabolism
Transcription Factors - genetics
Transcription Factors - metabolism
Transcriptome
uridylation
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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. [Display omitted] •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 Yi et al. show that the CCR4-NOT complex is a generic deadenylase and its two catalytic subunits have distinct activities regarding PABPC: CAF1 trims PABPC-free A tails while CCR4 removes PABPC-bound A tails. PABPC coordinates mRNA deadenylation and decay in a timely order by promoting deadenylation and blocking precocious decay.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2018.05.009