Canceling the stop signal will cure a third of hereditary diseases?
A new method of changing the genetic code: targeted RNA conductors modify the matrix RNA
LifeSciencesToday based on the materials of the University of Rochester:
Changing Genetic ‘Red Light’ to Green Holds Promise for Treating Disease
In an article recently published in the journal Nature (Converting nonsense codons into sense codons by targeted pseudouridylation), scientists from the University of Rochester Medical Center described a completely new method of changing the genetic code. The results of their experiments are of great importance: the new method can help change the course of the most severe genetic diseases, such as cystic fibrosis, muscular dystrophy and many forms of cancer.
A genetic code is a set of instructions in a gene that "tell" a cell how to make a specific protein. The central role in the process of protein synthesis is played by matrix RNA (mRNA), which receives instructions from DNA and guides further biochemical steps. For the first time, scientists have managed to artificially modify the matrix RNA and, thus, change the original instructions. The end result: a protein other than the one encoded in the gene.
"The ability to manipulate the protein production of a particular gene is a new miracle of modern medicine," says Robert Bambara, PhD, head of the Department of Biochemistry and Biophysics at the University of Rochester Medical Center. "This is really a very powerful concept that can be used to try to suppress the tendency to develop some of the most severe and sometimes fatal genetic diseases that can change a person's life forever."
Protein synthesis is far from an ideal process. Frequent mutations in DNA and matrix RNA lead to the production of proteins with a broken structure, which can potentially harm the body. In this study, scientists focused on a common type of mutation that leads to the fact that in the middle of the matrix RNA molecule there is a stop codon - a triplet of nucleotides that gives the ribosome the command to stop protein synthesis. As a result, such a protein turns out to be shortened and non-functional.
Scientists managed to change the matrix RNA in such a way that the stop signal was converted into a signal to continue reading. Figuratively speaking, the red light of the traffic light was switched to green. As a result, the cell was able to read the genetic instructions to the end and create a normal protein. The researchers reproduced these results both in vitro and in vivo – in living yeast cells.
"This is a remarkable result," said the head of the study, Professor of biochemistry and biophysics, Ph.D. Yi–Tao Yu (Yi-Tao Yu). "No one has ever thought that it is possible to change the premature stop codon in the way we did and allow the broadcast to go to the end without interruption."
It is difficult to overestimate the results obtained, since according to the latest data, premature stop codons leading to the synthesis of incomplete proteins are the cause of about a third of genetic diseases. The new method will allow scientists to develop therapeutic strategies that can help the body "cancel" premature stop codons and produce adequate amounts of complete proteins, the absence of which causes diseases such as cystic fibrosis and contributes to the development of various types of cancer.
To modify the matrix RNA, Professor Yu, together with the first author of the article, Ph.D. John Karijolich, used another type of RNA – guide RNA (guide RNA, gRNA). A guide RNA is a short RNA that binds to specific sequences of matrix RNA and allows modifying one of its specific sections.
"RNA conductors give us huge opportunities to influence a specific part of the genome and purposefully change it," notes Professor Bambara.
Scientists created an artificial gRNA and "programmed" it: gRNA had to find its target – a specific stop codon in one of the mRNAs - and modify it.
"The fact that this strategy works – the dRNA we created found its way to its target, the stop codon, and caused the desired change in structure - is just wonderful. It was believed that RNA conductors did not have access to mRNA, so no one believed that matrix RNA could become a target for modification by RNA conductors," says Karijolic. "Our experiments raise the question of whether such a process can occur naturally."
"In previous studies, other ways of modifying the genetic code were presented, but our method is unique in that the modification is carried out at the RNA level and is highly specific. We can trigger the expression of artificial dRNA in the cell and direct it to modify a single site, and only this site," explains Professor Yu.
Such modification of the matrix RNA may be another mechanism that human cells use to create various types of proteins. Considering our complexity, humans have surprisingly few genes. Scientists are well aware that most human genes encode more than one protein. Perhaps mRNA modification is one of those still misunderstood ways in which the human body is able to synthesize such a huge protein diversity.
Professor Yu plans to continue his research and establish whether targeted modification of the matrix RNA occurs naturally and, if so, find out the details of this process.
Portal "Eternal youth" http://vechnayamolodost.ru30.06.2011