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Another unexpected but more than useful feature of antisense RNA

Antisense RNA is showing great potential for future treatment of severe diseases such as cancer, HIV, CMV… Recently, another unexpected feature of antisense RNA is discovered - it actually can stimulate protein synthesis!

All proteins in the human body are produced as a result of complex and well controlled machinery that include information written in the DNA, mRNA molecule that transfer genetic information from DNA to the ribosome, and ribosomes, which act like a protein factory where nucleotide chain will be converted in the amino acids chain in the process called translation. All these cascade events are supported by numerous enzymes. Human organism produces around 25 000 coding mRNA molecules which means that each one of them can be turned into protein. This set of mRNA is known as transcriptome. Each mRNA has its own antisense matching pair. Antisense RNAs were considered to be a junk RNA because they don't produce valid proteins. They are implicated in negative regulation of the transcription through binding to their complementary (coding) mRNA. Result of binding is a double stranded RNA that will be recognized as abnormal and harmful for the cells and thus it will be eliminated as soon as possible via enzymatic degradation. 70% of all RNA in the cell is antisense RNA, which tells us that this RNA must be very important for normal cell functioning. Scientists believed that all details and tricky parts associated with genetic expression and protein synthesis are well known, but as it usual happen in the science, new information and latest discoveries are revealed by accident.

Group of Italian scientists studied a gene associated with Parkinson disease in its mutated form. This gene has same structure and function in human and mouse. It is called Uchl1 and it codes ubiquitin carboxyl-terminal esterase L1, which is associated with both normal brain function and neurodegeneration. Using a mouse model, scientists discovered that Uchl1 has more than one class of antisense RNA and even a bigger surprise came later when they discover that these antisense molecules doesn’t work the way they expected them to do - instead being focused on suppression of mRNA translation, they stimulate it. This was the first time that one antisense molecule became recognized as stimulator of translation that could regulate protein synthesis positively. Mechanism of this stimulation is really simple: antisense RNA increases association between mRNA and ribosome through additional set of nucleotides called SINEB2 element. Antisense molecules are longer than mRNA because they contain part that doesn’t match with sense RNA but accelerate protein synthesis through enhancing the binding of double stranded RNA with ribosome. Other part of the molecule is classical antisense RNA complementary with mRNA. Once mRNA and antisense RNA join together, this complex will bind to the ribosome and translation will start.

How this discovery can be exploited further? Binding of the SINEB2 element with ribosome is unrelated to the remaining part of the antisense molecule, which means that these elements can be applied universally to enhance protein synthesis of each therapeutically or industrially needed protein simply by adding SINEB2 element to the antisense RNA of interest. They are already available commercially under the name SINEUPs (SINE for SINE sequence they contain, and UP because they up-regulate protein production). Their main advantages are fast and efficient protein production (they increase protein synthesis 5-10 times) and lower cost compared to standard methods used. Also, work with these molecules doesn't demand too much effort. Kit contains universal SINEUP in combination with SINEUP-based protein-coding cloning vector. SINEUP can be transfected into desired cell line or in vivo with gene of interest, or it can be inserted alone to increase endogenous protein levels.

SINEUPs are the only known antisense molecules that regulate protein synthesis by enhancing translation directly. Discovery of SINEUPs reduced the cost of protein manufacture and opened some new fields of research. Modern medicine pays a lot of attention to recombinant proteins and SINEUPS would allow faster and cheaper production of already known medically valuable proteins. It will also enhance research and provide even more terapeutics that could improve human health. Since SINEUPs can increase production of numerous mammalian proteins, they can also be applied beyond medical and pharmaceutical field. Proteins are important part of agriculture, animal food, play important role in detergent production, in brewing industry. As with any other high tech - possibilities are endless.