Park Joha, Kim Myeonghwan, Yi Hyerim, Baeg Kyungmin, Choi Yongkuk, Lee Young-Suk, Lim Jaechul, Kim V Narry
Center for RNA Research, Institute for Basic Science, Seoul, Korea.
School of Biological Sciences, Seoul National University, Seoul, Korea.
Nat Struct Mol Biol. 2023 Mar;30(3):330-338. doi: 10.1038/s41594-023-00930-y. Epub 2023 Feb 27.
Deadenylation generally constitutes the first and pivotal step in eukaryotic messenger RNA decay. Despite its importance in posttranscriptional regulations, the kinetics of deadenylation and its regulation remain largely unexplored. Here we identify La ribonucleoprotein 1, translational regulator (LARP1) as a general decelerator of deadenylation, which acts mainly in the 30-60-nucleotide (nt) poly(A) length window. We measured the steady-state and pulse-chased distribution of poly(A)-tail length, and found that deadenylation slows down in the 30-60-nt range. LARP1 associates preferentially with short tails and its depletion results in accelerated deadenylation specifically in the 30-60-nt range. Consistently, LARP1 knockdown leads to a global reduction of messenger RNA abundance. LARP1 interferes with the CCR4-NOT-mediated deadenylation in vitro by forming a ternary complex with poly(A)-binding protein (PABP) and poly(A). Together, our work reveals a dynamic nature of deadenylation kinetics and a role of LARP1 as a poly(A) length-specific barricade that creates a threshold for deadenylation.
去腺苷酸化通常是真核生物信使核糖核酸（mRNA）降解的第一步且是关键步骤。尽管其在转录后调控中具有重要性，但去腺苷酸化的动力学及其调控在很大程度上仍未得到探索。在此，我们鉴定出La核糖核蛋白1、翻译调节因子（LARP1）是去腺苷酸化的一般减速因子，其主要作用于30至60个核苷酸（nt）的聚腺苷酸（poly(A)）长度窗口。我们测量了聚腺苷酸尾长度的稳态和脉冲追踪分布，发现去腺苷酸化在30至60 nt范围内减缓。LARP1优先与短尾结合，其缺失会导致去腺苷酸化加速，且特异性地发生在30至60 nt范围内。一致地，LARP1敲低导致信使核糖核酸丰度整体降低。LARP1在体外通过与聚腺苷酸结合蛋白（PABP）和聚腺苷酸形成三元复合物来干扰CCR4-NOT介导的去腺苷酸化。总之，我们的工作揭示了去腺苷酸化动力学的动态性质以及LARP1作为聚腺苷酸长度特异性屏障的作用，该屏障为去腺苷酸化设定了一个阈值。
