AsianScientist (Aug. 2, 2018) – In a study published in Science, a research group in South Korea has found that the tails of messenger RNA (mRNA) contain a wider variety of nucleotides than previously thought.
mRNA is a delicate molecule with an important function—it carries genetic information contained in DNA out of the nucleus to produce proteins. When a gene is transcribed into mRNA, the mRNA is equipped with a tail that acts like a shield against premature degradation. Cells can control mRNA degradation to reliably curb the amount of specific proteins at any desired time.
Scientists at the Center for RNA research at the Institute for Basic Science (IBS) in South Korea have identified how mixed mRNA tails—made of different nucleotides—protect mRNA from degradation for longer periods of time. Until recently, mRNA tails were thought to be merely a chain of hundreds of adenosine (A) monophosphate nucleotides, and was thus commonly called the poly(A) tail.
Previously, the researchers discovered that the mRNA tail is not limited to A. They developed a high-throughput sequencing method, TAIL-seq, to accurately measure the length of poly(A) tails at a genome-wide scale. They found out that nucleotides other than A, like guanosine (G), uridine (U) and cytosine (C), decorated the tail end. Mixed tails were reported in an evolutionarily broad range of species, including humans, mice, frogs and fish.
In this current study, researchers found out that some of the enzymes that insert A to the tail are able to add also G, U, and C, creating a mixed tail. In particular, nucleotidyltransferase TENT4A/B intermittently adds Gs when extending the mRNA tail.
Interestingly, Gs are located mainly at the very end of the mRNA tail, or at the next to last position. This can be explained by the fact that the enzymes that prune the poly(A) tails stall when they encounter a G, rather than an A, at the end of the tail. In other words, the research team found out that the addition of G may slow down the trimming of the tail, thereby protecting it.
“Non-adenosines added by TENT4A/B have a considerable stalling effect. Just one is enough to counteract poly(A) trimming enzymes and stabilize the mRNA,” explained Dr. Lee Young-suk of IBS, one of the authors of the study.
The level of mRNAs with mixed tails was also found to be reduced in cells lacking TENT4A/B.
“The mRNA tail has been considered a pure stretch of As with little informational content, except for its length. However, this study proves that even tails of the same length can have different composition, and a mixed tail degrades more slowly than the pure poly(A) tail,” said Professor Narry Kim, corresponding author of the study and director of the Center for RNA research at IBS.
“Through this study, we can understand the life history of complex mRNA by revealing a new kind of mRNA protection mechanism that was not known before.”
In the future, the team would like to expand their research to various biological systems, and to understand how misbehaving tailing mechanisms can lead to various diseases. In addition, they would like to develop a RNA-based gene therapy method that utilizes the mixed tailing effect in cells to enhance mRNA stability.
The article can be found at: Lim et al. (2018) Mixed Tailing by TENT4A and TENT4B Shields mRNA from Rapid Deadenylation.
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Source: Institute for Basic Science.
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