In the course of studying Parkinson's disease, an international research team obtained a new discovery that could improve industrial protein synthesis for therapeutic use. They managed to understand a new function of non-protein-coding RNA: the activity of such non-coding RNA called "antisense" can increase the protein synthesis activity of the coding gene. Related results were published in the October 14th "Nature" (Nature) magazine.
To synthesize proteins, DNA requires RNA molecules to act as short "short transcripts" of genetic information. All these collections of RNA molecules are called "transcriptomes". In the human transcriptome, there are about 25,000 coding RNA sequences (such as those involved in the synthesis process), and there is a larger number of non-coding RNA sequences. Some of these RNAs are called "antisense" because they are complementary to the coding RNA sequence called "sense" (a pair of sense and antisense RNA can be regarded as a zipper).
The RIKEN Omics Science Center in Yokohama, Japan has discovered that many protein-coding genes have corresponding antisense RNAs. The new study, published in the journal Nature by the Italian International Institute for Advanced Studies (SISSA) research team, now finds that a specific type of antisense RNAs overlaps with protein-coding RNAs, facilitating translation. This is contrary to the current view that antisense RNAs are generally associated with negative regulation of protein translation.
Most mammalian genomes are transcribed to produce non-coding RNA. The RIKEN FANTOM project earlier proved that the largest output of the genome consists of non-coding RNAs. More than 70% of mRNAs in cells are related to non-coding antisense RNAs, which are generally thought to negatively inhibit transcription or translation.
In a special collaborative study based on RIKEN FANTOM sense-antisense cDNA clones, including SISSA and RIKEN Omics Science Center, a group found that a class of non-coding antisense RNAs did the opposite of what is currently known: Translation of paired mRNAs. The researchers discovered this function by studying the antisense of Uchl1 mRNA. Uchl1 is a mouse gene that is associated with brain function and neurodegenerative diseases. Using RIKEN's bioinformatics and data mining, the research team also found that the antisense of Uchl1 RNA is not a single situation, but represents a large class of mammalian antisense RNAs whose function is to promote translation. This is the first report that an antisense RNA enhances protein production and works in both mouse and human cells, and is expected to have similar functions in other organisms.
This mechanism of promoting translation is based on enhancing the binding of mRNAs to ribosomes, which is mediated by a repeat sequence in Uchl1 RNA antisense, a SINEB2 element, which is placed in an inverted direction of this non-coding RNA on. This specificity is conferred by short antisense RNA sequences that hybridize to the initial part of the protein-coding mRNA.
Why is it an important discovery?
Little is known about "long-chain, non-coding" RNAs in the past, and this new study clarifies some of these molecules. SISSA professor Stefano Gustincich said: "We are focusing on the Uchl1 gene, its mutations are related to some genetic forms of Parkinson's disease. We see that the non-coding antisense RNA that matches this gene is composed of two parts, A true antisense fragment and SineB2 sequence that matches the protein-sense sense RNA. The antisense fragment functions as a 'lock'. The specific coding RNA key of this gene can be inserted, and the other fragment promotes protein synthesis.
If you change the antisense fragment with analogs of other genes, the SineB2 sequence will maintain its function of promoting new genes. "This is important because it means that the functions of sineB2 can be used to promote protein production in industrial synthesis processes for clinical use," Gustincich explained.
Piero Carninci, head of the RIKEN OSC team, said: "We are very pleased to see more than one function of long-chain non-coding RNAs. Since the initial discovery that most genomes produce so many non-coding RNAs, there has been widespread doubt about the function of these RNAs. This is a milestone study, and found a new class of non-coding RNAs, which have important regulatory functions that can promote protein translation. In addition, this function is mediated by repetitive elements, so far repetitive elements are generally considered It ’s the “junk†part of the genome, suggesting that the majority of the genome is “junk†should be revisited. After all, it is possible to embed functions in any part of the genome, but we do n’t know yet. â€
RIKEN and RIKEN startup company TransSINE Technologies are now committed to developing commercial applications of such special structures of antisense RNA.
These RNAs, called SINEUPs, can be engineered to promote translation of other proteins and target all proteins of industrial or therapeutic interest by changing overlapping antisense regions. Early target proteins will include therapeutic proteins such as antibodies or other soluble factors, as well as other basic research to understand gene function through expressed proteins. RIKEN believes that this work will be widely used.
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