The Central dogma of biology formulated by Francis Crick in the late 1950s, studying in the classical form: DNA—>RNA—>protein. But there is enough data to question the literal understanding this main principle of life.
The latest example: the June publication of Scientific Reports, Russian scientists from the Institute of Bioorganic chemistry Federal research and clinical center for physical-chemical medicine showed that a variety of isoforms of proteins in cells is much less than theoretically possible. Journalists were quick to report that changing the representation of the Central dogma of molecular biology. However, the dogma has changed for 70 years because the original was just a hypothesis. The word “dogma”, the Creator of the Creek was named because I liked the word! What is important is how and why changing the main hypothesis of molecular biology.
Too much RNA
Genetic information is transcribed from the coding sequences of the genome presents genes. Only a small part of the genome of eukaryotes (plants, animals, fungi) contains genes, and the main part presents the extended nucleotide sequences with unknown functions. In the human genome only covered a quarter of the genes and only 1% of DNA encodes information that is recorded in functional RNA molecules (part of the dogma “DNA–>RNA”). That is, 1% of genomic DNA contains information about all of the RNA molecules. Why the remaining 99%?
In recent years, it became clear that the intergenic stretches of DNA contain regulatory function: they contain the systems and elements ensuring fine tuning of the genes they turn on or off in specific tissues or at specific stages of development. With such contact elements of different complexes, which contain molecules of regulatory proteins and RNA. Even at this level, it is obvious that the model “DNA–>RNA–>protein” not fully working, since the bulk of DNA gives RNA the beginning, but has other functions.
Part of the gene encodes an RNA with regulatory functions. These RNAS do not contain information about the sequence of the protein, and mainly organize protein synthesis in the cell. The majority of these RNA components of ribosomes (ribosomal RNA) complexes, broadcasting, and molecules carrying amino acids (transfer RNA), necessary participants of the process of protein synthesis on the matrix RNA (translation). 90% of the total RNA of the cells fall into the following types.
Among the remaining 10% of RNA molecules presents all protein-encoding RNA, but even among these non-coding RNA molecules was found, in particular, the small nuclear RNAS. These RNA are necessary components of the complex splicing. Splicing — the removal of the primary RNA molecules non-coding sites (its introns are) and the serial connection of coding (exons); the result is a matrix RNA (mRNA) containing ready-to-read information about the sequence of the protein.
This complex prepares the precursors of mRNA to the synthesis of the correct protein by cutting out from the middle of RNA sequences that do not contain information on the composition of the protein, but containing regulatory elements. So that part of the dogma “RNA –> protein” has its limitations.
“Molecular quality control”
What do we know about the so-called “protein-coding” genes? In prokaryote cells (bacteria) for this type of genes it’s simple: on the matrix DNA are transcribed RNA molecules, their basis is the synthesis of protein molecules. Most often, the RNA molecules are ready for synthesis during transcription.
In eukaryotic cells everything is much more complicated: it is synthesized by the process of transcription of RNA molecules not ready for translation (protein synthesis), first they have to undergo several changes. A specific set of modifications introduced to the ends of RNA molecules (RNA and becomes stable, and falls in certain areas of the cells “protein factory”), from the middle of the molecules are cut out introns. No splicing and the joining of exons of a correct protein molecule to synthesize.
With the increasing complexity of the genomes of the contribution of splicing in the maturation process of mRNA increases: in yeast, only 4% of protein-coding gene undergoes splicing, in Drosophila — 83% and the person — 94%. The major part of human genes contain more than one intron in its composition and more than half of human genes can slayeroffice in several ways. So splicing is an additional regulatory mechanism that controls the number of “correct” RNA on the matrix which may start the synthesis of protein molecules.
In addition, splicing is often a kind of “quality control” of RNA molecules that regulates their stability. As well as alternative splicing leads to the formation on the basis of the same RNA molecule of different variants of Mature mRNA, it is a way to provide additional variety of proteins in the cell. This diversity is necessary for a better adaptability of the body: different isoforms of the protein can work in different types of cells, transported in different compartments, or to form different surface recognition of ligands, etc.
What “noise” genes
Not all isoforms of known proteins functions, and in many cases alternative playerowner RNA molecules fails to detect protein product. The authors of this article in Scientific Reports studying the products of alternative splicing in the model moss, found proteins for the most part alternative playerowner molecules of mRNA. In studies performed in other model organisms, for many playerowner alternative variants of mRNA and protein molecules were found.
It is possible that such molecules is a by — product regulation “the number of” gene expression, “gene noise”; or some isoforms of protein needed in extremely limited quantities.
In addition, many introns were genes are regulatory elements that control the splicing process, and there can be non-coding RNAS involved in cellular metabolism. So that the variety of isoforms, and even protein expression may be monitored directly by the RNA molecules without involvement of DNA.
With the development of genome sequencing technologies, more work on non-coding molecules of RNA. In the human genome described the huge pool of these RNA — “long” and “short”: they carry out important regulatory functions in the cell. These RNAS follow the stability of protein-coding RNAS that activate or repress genes, are sensors under different stresses. Functions the main part of non-coding RNAS is not yet described, is the whole world, without which the cell and the organism cannot exist.
Today, the accumulated data suggest that at the molecular level, life is a form of implementation of the functions of RNA. DNA stores the information, a protein responsible for cellular metabolism and life of the cell (and organism) is organized and monitored in the operational phase of RNA molecules.
There are even assumptions that RNA at the dawn of evolution was the first biopolymer, capable of reproducing itself. RNA, on the one hand, like DNA, is able to be a repository of genetic information (genomes a huge group of viruses represented RNA). With other famous and RNA with catalytic function, able to perform some of the functions of proteins. Supporters of the RNA world believe that the properties of RNA, allowing them to reproduce by its own enzymatic activity recorded in the nucleotide sequences information played a crucial role in the formation of the genetic apparatus of living organisms.
The time for such generalizations has not yet come. Scientists are only beginning to understand that the system they study for 100 years, is much more complicated than it seemed even 20 years ago.
Oksana Maksimenko, candidate of biological Sciences, Institute of gene biology, RAS
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