How to cut the R-loop
Scientists have learned how the body protects itself from the appearance of mutations in genes
"Open Science" based on the materials of the RNF press service
Russian biologists have found out that stress causes the appearance of numerous mutations in the synthesis of RNA, and described the mechanism preventing them. In the future, this may shed light on the nature of some hereditary diseases, including congenital deformities of bones. The study was carried out within the framework of a project supported by a grant from the Presidential Research Projects Program of the Russian Science Foundation, and its results are published in the journal Nuclear Acids Research (Velichko et al., Hypo-erotic stress induces R loop formation in nucleoli and ATR/ATM-dependent silencing of nuclear transcription).
Our hereditary information is stored in the form of genes, whose products – proteins – control all processes in the body. To implement the program, the body needs to read information from DNA and rewrite it into the form of RNA. This process is called transcription. Protein synthesis (translation) takes place on the RNA matrix, which is carried out by special molecular machines – ribosomes. They consist of protein and RNA encoded in ribosomal genes, which are considered the most actively transcribed - their transcription is the most effective.
During the work, the staff of the Institute of Gene Biology of the Russian Academy of Sciences and Lomonosov Moscow State University studied how stress affects the process of reading ribosomal genes. To do this, they subjected cultures of cancer and normal human cells to mild hypotonic stress, in which the cell volume increases as a result of ingestion of water.
"We found out that during hypotonic stress, abnormal structures - "R–loops" are formed in the areas of actively transcribing ribosomal genes," said one of the authors of the article Omar Kantidze, project leader, Doctor of Biological Sciences, head of the Genome Stability Laboratory of the Institute of Gene Biology of the Russian Academy of Sciences.
R-loops appear, in particular, due to a violation of the normal transcription process and are hybrids of DNA and RNA. When cells are stressed, the probability of such errors increases. R-loops are very dangerous because they often cause breaks in DNA and thereby provoke genomic instability. Then there are many mutations in the body that can lead to various diseases, including cancer.
In addition, the authors found a mechanism of protection against the formation of these structures and described it. Under conditions of hypotonic shock, the "doctor" protein TopBP1 recognizes R-loops and activates a special enzyme that suppresses transcription of ribosomal genes. As a result, mutations stop accumulating in the cell.
Scientists have also suggested that the Treacle protein serves as a kind of platform for the assembly of the "doctor" protein and the production of the enzyme, without which this protective mechanism simply does not work. The researchers note that mutations in this protein cause Treacher Collins syndrome, a congenital craniofacial deformity. It occurs in one in 50,000 infants and is characterized by the effect of a "sunken" face: a large nose, small lips and chin, in some cases – a cleft palate. Some patients have no hearing, as the structure of the ear is also deformed.
"We have described for the first time the mechanism of suppression of transcription of ribosomal genes under stress. The results of the work expand our understanding of the functional significance of the Treacle protein and its role in the cellular response to adverse factors. We hope that the study of these molecular mechanisms will help in understanding the nature, and possibly in the treatment of Treacher Collins syndrome," concluded one of the authors of the article Artem Velichko, senior researcher at the Genome Stability Laboratory of the Institute of Gene Biology of the Russian Academy of Sciences.
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