Gene regulation

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Parent
(Regulation of) gene expression
(regulation of) macromolecule metabolism
Subordinate
Epigenetic gene
regulation Regulation of transcription
Reg. Of mRNA processing
Regulation of translation
Reg. Of protein processing
Gene Ontology
QuickGO

In biology, gene regulation describes the control of the activity of genes , more precisely the control of gene expression . It determines whether the protein encoded by the gene is produced in the cell , at what time and in what quantity. There are various levels at which regulation can take place: “Gene expression” is the entire process of converting the information contained in the gene into the corresponding gene product. This process takes place in several steps. Regulatory factors can influence each of these steps and control the process.

In prokaryotes , gene regulation is used to a large extent to adapt to a changing environment, for example to a reduced supply of oxygen or a changing supply of nutrients. With the exception of protists, eukaryotic cells are less dependent on reacting to fluctuating environmental conditions, but have the difficult task of controlling the development of multicellular organisms . To do this, it must be ensured that the necessary genes are activated in the right tissue in the right cells at the right time. Once the expression program has been defined, it then has significantly less need for regulation in differentiated cells.

The basic principles of gene regulation are the same in all cells, but there are special features in both prokaryotes and eukaryotes. For example, genes in bacteria are often organized in operons , which are very rare in eukaryotes. Eukaryotes, on the other hand, have mechanisms for processing transcripts that offer additional starting points for regulatory factors.

In operon is divided into positive and negative regulatory regulation. In positive regulation, the RNA polymerase needs an activator that binds to the DNA so that transcription can take place. In negative regulation, a repressor binds to the DNA and the RNA polymerase cannot transcribe the gene. In addition, certain metabolites can activate the activators and repressors (activator / repressor can bind to the DNA) or inactivate them (activator / repressor dissociated from DNA). One speaks of induction when the binding of the metabolite leads to transcription (and thus gene expression) taking place (inactivation of the repressor or activation of the activator). Repression means that the substrate prevents gene expression (activator is inactivated or repressor is activated).

Steps of gene expression

The regulation is implemented in the following gene expression steps:

Chromatin

In eukaryotes, the genomic DNA is partially wrapped around histones . The modification of histones causes a change in the unfolded areas of the DNA that are available for transcription. The DNA methylation- inactivated genes in eukaryotes. Histone modification and DNA methylation are part of a cell's epigenetic code .

Initiation of transcription

By controlling the start of transcription, the general decision is made as to whether the gene is to be expressed (read) or not, and in some cases also how many mRNA molecules should be produced. This decision is made based on the regulatory sequences . These are areas of the DNA that can be in the immediate vicinity of the gene or further away (the promoter ), but which are not themselves transcribed. Proteins that activate or inhibit ( repress ) transcription can bind to these regulatory sequences . These key proteins are called transcription factors and they enable the cell to switch genes on and off through a basic mechanism. A transcription factor that promotes the binding of RNA polymerase is called an activator . A transcription factor that inhibits their binding is called a repressor . The corresponding repressive DNA sequences are called silencers .

After the binding of the specific transcription factors to the promoter or enhancer , there is a change in the conformation of the chromatin . This enables other proteins, so-called basal transcription factors, to also bind to the DNA. The basal transcription factors then recruit the RNA polymerase and the transcription of the gene is started. The specificity factors are proteins that modulate the binding specificity of the RNA polymerase. If a repressor binds to the regulatory DNA areas, it prevents further transcription factors from accumulating and thus prevents activation of the gene. Another form of repression is what is known as transcriptional interference . A second promoter is located in front of the promoter of the gene. If this is active, the RNA polymerase attaches to it and synthesizes non-coding RNA . This transcription prevents the actual gene from being transcribed. Catabolite repression is a special case of transcription regulation .

Termination of the transcription

For the termination of transcription, various regulatory mechanisms have developed in prokaryotes and eukaryotes. The efficiency of the termination is decisive for how many mRNA molecules can arise from the gene, because if the polymerase does not fall off the DNA strand quickly enough, roughly speaking, the next polymerase molecule cannot move up and the production of the mRNA Molecules is slowed down.

Termination in prokaryotes

In the case of prokaryotes, a distinction is made between "Rho-independent" and "Rho-dependent" termination. There is also a mechanism in which the polymerase falls off the DNA again soon after the start of transcription, called attenuation .

  • Simple termination: Rho-independent or simple termination uses termination sequences at the end of the gene or in the 3 'UT area of the transcript. These sequences consist of a GC-rich segment and a series of uridine residues and can form a hairpin structure , followed by several uridines to bind Hfq . This can be imagined as a loop that is created by the fact that nucleotides of an RNA segment are linked with nucleotides of the same strand by internal base pairing and thus form their stem with double strands. The formation of the hairpin loop acts back on the RNA polymerase, which has just generated these sequences, so that it stops and detaches itself from the DNA strand template with the PolyU section of the mRNA. These RNAs do not have a polyA tail.
  • Rho-dependent termination: Rho-dependent termination uses another protein, the Rho factor . It forms a hexameric complex around single-stranded RNA, so that around 70 to 80 nucleotides of the RNA strand are wrapped around as the central axis. With the consumption of ATP , the Rho factor then initially moves along the nascent (emerging) mRNA until it meets the RNA polymerase. There it comes into contact with the DNA, separates the DNA-RNA hybrid produced by the RNA polymerase, similar to a helicase , and thus also the polymerase from the DNA template. The RNA polymerase falls off and transcription is finished. The Rho factor has to move faster along the mRNA than the polymerase that forms it. Since the polymerase does not move uniformly along the DNA and slows it down a little in between individual RNA synthesis steps, the Rho factor is able to catch up.
  • Attenuation : In the case of attenuation , a transcription that has started is terminated prematurely if the mRNA just formed forms a hairpin-shaped secondary structure as a termination signal through internal base pairing . The RNA polymerase then detaches from the DNA template even before structural genes have been read, because the attenuator sequence is in the 5 'UT region at the beginning of the transcript. In addition to those for the possible termination signal, this area then often contains several further regulatory sequences that can prevent its formation under certain conditions and thus allow transcription. This can be the case, for example, if a ribosome , which moves with a delay, takes up certain positions on the mRNA segment that has already been formed, which make folding into the terminating hairpin structure impossible.

Termination in eukaryotes

The three different eukaryotic RNA polymerases (I, II and III) use different termination mechanisms that have not yet been particularly well studied. However, some similarities and differences to termination in bacteria are known:

  • The RNA polymerase I, which transcribes rRNA genes, requires a Rho-like termination factor, which does not bind to the RNA, but to the DNA downstream.
  • The RNA polymerase II, which transcribes the mRNA, probably only stops transcription when the polyadenylation takes place (see next section).
  • The RNA polymerase III, the tRNA transcribed genes, terminates transcription by the incorporation of a number of uracil - nucleotides .

RNA processing

Capping

When capping, 7-methyl-guanosine is synthesized at the 5 'end of the pre-mRNA , which influences the stability and later translation of the RNA. The 5 'cap structure facilitates the attachment of the finished mRNA to the ribosome during translation (initiation).

Polyadenylation

Almost all mRNAs from animal cells have a poly (A) tail. The process of attaching this tail is known as polyadenylation. Similar to the termination of transcription, the strength of the transcription depends on the efficiency of the polyadenylation mechanism. If the attachment of the poly (A) tail does not work properly, the mRNA is not accumulated in the cell nucleus, but rather quickly broken down. This is where regulatory factors can come into play.

Splice

Splicing removes introns from the pre-mRNA and joins the remaining exons together. For this process, which is carried out by the spliceosome , there are alternatives for many genes, also known as alternative splicing . Regulatory factors determine which introns should be spliced ​​and thus determine what the finished mRNA will look like.

Transport into the cytoplasm

The mRNA is transported into the cytoplasm through pores in the nuclear envelope . Only fully processed mRNAs are channeled through the nuclear pore with the 5 'end first and immediately occupied with ribosomes in the cytoplasm. For this purpose, the mRNA is combined with various proteins to form an hnRNP complex that can migrate through the nuclear pores as a finished mRNP . The efficiency of this process determines the speed and the amount of finished mRNAs that reach the cytoplasm and can be regulated by factors.

Initiation of translation

The beginning of translation is the most important regulatory step in some genes, but hardly plays a role in others. In both eukaryotes and prokaryotes, a pre-initiation complex consisting of various proteins is formed which interacts with the small subunit of a ribosome. This complex then recognizes the translation start site. The possibilities of regulation are again very diverse. They range from the use of specific initiation factors to a general shutdown of initiation, which can be achieved by phosphorylating a serine residue of a protein of the pre-initiation complex (eIF2).

The translation of some mRNAs can also be blocked by antisense RNAs , which complementarily attach to the 5 'region of the RNA and thereby prevent the binding of the small ribosomal subunit. Also microRNAs play an important role in the translational regulation. During the translation there are e.g. B. in prokaryotes with the trp -operon the attenuation as a regulatory mechanism.

Stability of the mRNA

After the initiation of transcription and (for some genes) the initiation of translation, the regulation of the half-life of an mRNA is another regulatory process. The concentration of an mRNA depends on how quickly it is produced and how quickly it is broken down again. If an mRNA is very stable, protein production can continue long after the gene has been inactivated. A short-lived mRNA is therefore advantageous for proteins that need to be "switched off" quickly if necessary, i.e. no longer be present. B. with AUUUA sequences that accelerate degradation by binding RNases . The stability of an mRNA is determined, among other things, by the fact that several AUUUA sequences occur in the untranslated 3 'area of ​​the transcript. The more of it there are, the faster the RNA is broken down. Another important factor for the stability of the mRNA is the length of the poly (A) tail. The shorter this is, the shorter the half-life. Another mechanism that controls mRNA stability is nonsense-mediated mRNA decay , which recognizes premature stop codons in the mRNA and prevents their expression as truncated proteins.

Most bacterial mRNAs only have a half-life of a few minutes. Differentiated eukaryotic cells largely have less need for gene regulation (see above), the mRNA molecules of many genes achieve half-lives of several hours. Other eukaryotic genes that are only needed for a short time (for example hormones or cytokines ) are expressed in bursts.

Protein stability

In short-acting genes, proteins contain amino acids or amino acid sequences that accelerate the breakdown of a protein, e.g. B. certain amino acids according to the N-End Rule , PEST sequences or protease cleavage sites .

Epigenetic Regulation

There are also genes in which the information about whether the gene should be activated or repressed in the daughter cells is not present directly in the gene or is mediated by the gene, but rather through the transcription factors that regulate it. The transcription factors are, so to speak, “inherited”. Epigenetics and imprinting deal with these mechanisms .

Special regulatory mechanisms

Certain genes are always expressed and therefore have no need for regulation; these are referred to as housekeeping genes .

Gene regulatory areas

In the gene or belonging to the gene there are certain areas that are responsible for regulation. These are

literature

  • James E. Darnell , Harvey Lodish, David Baltimore : Molecular Cell Biology . de Gruyter, Berlin et al. 1993, ISBN 3-11-011934-X (4th edition. Harvey Lodish: Molecular Cell Biology. Spectrum Akademischer Verlag, Heidelberg et al. 2001, ISBN 3-8274-1077-0 ).
  • Benjamin Lewin: Molecular Biology of Genes . Spektrum Akademischer Verlag, Heidelberg et al. 1998, ISBN 3-8274-0234-4 .
  • William S. Klug, Michael R. Cummings, Charlotte A. Spencer: Genetics . 8th, updated edition 2007, pp. 410-411, ISBN 978-3-8273-7247-5 .
  • Donald Voet, Judith G. Voet: Biochemistry. 3rd edition, John Wiley & Sons, New York 2004. ISBN 0-471-19350-X .
  • Bruce Alberts , Alexander Johnson, Peter Walter, Julian Lewis, Martin Raff, Keith Roberts: Molecular Biology of the Cell , 5th Edition, Taylor & Francis 2007, ISBN 978-0815341062 .

Individual evidence

  1. ↑ H. Otaka, H. Ishikawa, T. Morita, H. Aiba: PolyU tail of rho-independent terminator of bacterial small RNAs is essential for Hfq action. In: Proceedings of the National Academy of Sciences . Volume 108, Number 32, August 2011, pp. 13059-13064, ISSN  1091-6490 . doi : 10.1073 / pnas.1107050108 . PMID 21788484 . PMC 3156202 (free full text).
  2. ↑ P. Regnier, E. Hajnsdorf: The interplay of Hfq, poly (A) polymerase I and exoribonucleases at the 3 'ends of RNAs Resulting from Rho-independent termination: A tentative model. In: RNA biology. Volume 10, Number 4, April 2013, pp. 602-609, ISSN  1555-8584 . doi : 10.4161 / rna.23664 . PMID 23392248 . PMC 3710367 (free full text).
  3. ↑ M. Boudvillain, M. Nollmann, E. Margeat: Keeping up to speed with the transcription termination factor Rho motor. In: Transcription. Volume 1, Number 2, 2010 Sep-Oct, pp. 70-75, ISSN  2154-1272 . doi : 10.4161 / trns.1.2.12232 . PMID 21326894 . PMC 3023631 (free full text).
  4. ↑ M. Boudvillain, N. Figueroa-Bossi, L. Bossi: Terminator still moving forward: expanding roles for Rho factor. In: Current Opinion in Microbiology. Volume 16, Number 2, April 2013, pp. 118-124, ISSN  1879-0364 . doi : 10.1016 / j.mib.2012.12.003 . PMID 23347833 .
  5. ↑ Jeremy M. Berg, John L. Tymoczko, Lubert Stryer : Biochemistry. 6 edition, Spektrum Akademischer Verlag, Heidelberg 2007. ISBN 978-3-8274-1800-5 . (free full text access) .
  6. ↑ Jeremy M. Berg, John L. Tymoczko, Lubert Stryer : Biochemistry. 6 edition, Spektrum Akademischer Verlag, Heidelberg 2007. ISBN 978-3-8274-1800-5 . (free full text access) .