Journal Article

The molecular basis of coupling between poly(A)-tail length and translational efficiency

Xiang, Kehui, Bartel, David P

2021

Overview

In animal oocytes and early embryos, mRNA poly(A)-tail length strongly influences translational efficiency (TE), but later in development this coupling between tail length and TE disappears. Here, we elucidate how this coupling is first established and why it disappears. Overexpressing cytoplasmic poly(A)-binding protein (PABPC) in Xenopus oocytes specifically improved translation of short-tailed mRNAs, thereby diminishing coupling between tail length and TE. Thus, strong coupling requires limiting PABPC, implying that in coupled systems longer-tail mRNAs better compete for limiting PABPC. In addition to expressing excess PABPC, post-embryonic mammalian cell lines had two other properties that prevented strong coupling: terminal-uridylation-dependent destabilization of mRNAs lacking bound PABPC, and a regulatory regime wherein PABPC contributes minimally to TE. Thus, these results revealed three fundamental mechanistic requirements for coupling and defined the context-dependent functions for PABPC, which promotes TE but not mRNA stability in coupled systems and mRNA stability but not TE in uncoupled systems. Cells are microscopic biological factories that are constantly creating new proteins. To do so, a cell must first convert its master genetic blueprint, the DNA, into strands of messenger RNA or mRNA. These strands are subsequently translated to make proteins. Cells have two ways to adjust the number of proteins they generate so they do not produce too many or too few: by changing how many mRNA molecules are available for translation, and by regulating how efficiently they translate these mRNA molecules into proteins. In animals, both unfertilized eggs and early-stage embryos lack the ability to create or destroy mRNAs, and consequently cannot adjust the number of mRNA molecules available for translation. These cells can therefore only regulate how efficiently each mRNA is translated. They do this by changing the length of the so-called poly(A) tail at the end of each mRNA molecule, which is made up of a long stretch of repeating adenosine nucleotides. The mRNAs with longer poly(A) tails are translated more efficiently than those with shorter poly(A) tails. However, this difference disappears in older embryos, when both long and short poly(A) tails are translated with equal efficiency, and it is largely unknown why. To find out more, Xiang and Bartel studied frog eggs, and discovered that artificially raising levels of a protein that binds poly(A) tails, also known as PABPC, improved the translation of short-tailed mRNAs to create a situation in which both short- and long-tailed mRNAs were translated with near-equal efficiency. This suggested that short- and long-tailed mRNAs compete for limited amounts of the translation-enhancing PABPC, and that long-tailed mRNAs are better at it than short-tailed mRNAs. Further investigation revealed that eggs also had to establish the right conditions for PABPC to enhance translation and had to protect mRNAs not associated with PABPC from being destroyed before they could be translated. Overall, Xiang and Bartel found that in eggs and early embryos, PABPC and poly(A) tails enhanced the translation of mRNAs but did not influence their stability, whereas later in development, they enhanced mRNA stability but not translation. This research provides new insights into how protein production is controlled at different stages of animal development, from unfertilized eggs to older embryos. Understanding how this process is regulated during normal development is crucial for gaining insights into how it can become dysfunctional and cause disease. These findings may therefore have important implications for research into areas such as infertility, reproductive medicine and rare genetic diseases.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Cell lines / Cells / Chromosomes and Gene Expression / Embryos / Gene expression / Genetic translation / Messenger RNA / mRNA stability / Nucleotides / Oocytes / PABPC1 / Poly(A) / poly(A) tail / Poly(A)-binding protein / Protein binding / Proteins / regulation of mRNA stability / regulation of translation / Standard deviation / terminal uridylation / Translation / Xenopus oocytes / Yeast