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单核苷酸分辨率下混合 poly(A) 尾的去腺苷酸化动力学。

Deadenylation kinetics of mixed poly(A) tails at single-nucleotide resolution.

机构信息

Center for RNA Research, Institute for Basic Science, Seoul, Republic of Korea.

Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.

出版信息

Nat Struct Mol Biol. 2024 May;31(5):826-834. doi: 10.1038/s41594-023-01187-1. Epub 2024 Feb 19.

DOI:10.1038/s41594-023-01187-1
PMID:38374449
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11102861/
Abstract

Shortening of messenger RNA poly(A) tails, or deadenylation, is a rate-limiting step in mRNA decay and is highly regulated during gene expression. The incorporation of non-adenosines in poly(A) tails, or 'mixed tailing', has been observed in vertebrates and viruses. Here, to quantitate the effect of mixed tails, we mathematically modeled deadenylation reactions at single-nucleotide resolution using an in vitro deadenylation system reconstituted with the complete human CCR4-NOT complex. Applying this model, we assessed the disrupting impact of single guanosine, uridine or cytosine to be equivalent to approximately 6, 8 or 11 adenosines, respectively. CCR4-NOT stalls at the 0, -1 and -2 positions relative to the non-adenosine residue. CAF1 and CCR4 enzyme subunits commonly prefer adenosine but exhibit distinct sequence selectivities and stalling positions. Our study provides an analytical framework to monitor deadenylation and reveals the molecular basis of tail sequence-dependent regulation of mRNA stability.

摘要

信使 RNA 多聚（A）尾的缩短，即脱腺苷酸化，是 mRNA 降解的限速步骤，在基因表达过程中受到高度调控。在脊椎动物和病毒中已经观察到多聚（A）尾中掺入非腺苷酸，即“混合尾化”。在这里，为了定量混合尾的影响，我们使用体外脱腺苷酸化系统，在单核苷酸分辨率下对脱腺苷酸化反应进行了数学建模，该系统由完整的人 CCR4-NOT 复合物重新组成。应用该模型，我们评估了单个鸟嘌呤、尿嘧啶或胞嘧啶的破坏影响，分别相当于大约 6、8 或 11 个腺苷酸。CCR4-NOT 在相对于非腺苷酸残基的 0、-1 和-2 位置处停滞。CAF1 和 CCR4 酶亚基通常偏爱腺苷酸，但表现出不同的序列选择性和停滞位置。我们的研究提供了一种分析框架来监测脱腺苷酸化，并揭示了 mRNA 稳定性的尾部序列依赖性调节的分子基础。

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