PABP 通过与 CCR4-NOT 复合物相互作用促进 mRNA 衰减并阻止早期衰变。

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

机构信息

Center for RNA Research, Institute for Basic Science, Seoul 08826, Korea; School of Biological Sciences, Seoul National University, Seoul 08826, Korea.

出版信息

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

DOI:10.1016/j.molcel.2018.05.009

PMID:29932901

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.

摘要

脊椎动物中已知存在多种去腺苷酶，包括 PAN2-PAN3（PAN2/3）和 CCR4-NOT（CNOT）复合物以及 PARN，但它们的功能仍不清楚。此外，多聚腺苷酸结合蛋白（PABP）的作用也不清楚，这限制了我们对去腺苷化机制的理解。本研究表明，CNOT 是细胞质多聚 A RNA 的主要非特异性去腺苷酶，而 PABP 可促进去腺苷化，同时防止过早的尿苷酸化和降解。PAN2/3 选择性地修剪长尾巴（>∼150nt），对转录组的影响最小，而 PARN 则不影响 mRNA 的去腺苷化。CAF1 和 CCR4 是 CNOT 的催化亚基，显示出不同的活性：CAF1 修剪裸露的多聚 A 片段，并被 PABPC 阻断，而 CCR4 被 PABPC 激活以缩短 PABPC 保护的序列。CAF1 和 CCR4 的协同作用描绘了沿缩短尾巴出现的∼27nt 周期性 PABPC 足迹。本研究揭示了去腺苷酶和 PABPC 的不同功能，重新描绘了 mRNA 去腺苷化和调控的观点。