Fundamentals of Molecular Biology - V.I. Rezyapkin 2009

Regulation of Gene Expression
Regulation at the Level of mRNA Degradation

The rate of synthesis of each specific protein depends on the intracellular concentration of its corresponding mRNA. Naturally, the higher the mRNA concentration, the greater the rate of Synthesis of the protein encoded by it. The amount of mRNA in a Cell is determined not only by its rate of synthesis, but also by the intensity of its degradation. The half-life of prokaryotic mRNA is only a few minutes, whereas in eukaryotes this metric ranges from several tens of minutes to several days. Consequently, mRNA degradation plays a much more prominent role in the Introduction/30.html">Regulation of Gene Expression in Eukaryotes than in prokaryotes.

As an example, let us examine The Significance of controlled mRNA degradation in regulating transferrin receptor synthesis. Regulation of transferrin receptor synthesis

The rate of iron uptake into a cell depends on the presence of transferrin receptors—iron-transport Proteins—on its surface. When cellular iron levels are low, transferrin receptors are synthesized efficiently. These newly synthesized receptor molecules are integrated into The Cell membrane, facilitating iron influx into the cell. Conversely, when iron content is high, the mRNA of the transferrin receptor undergoes degradation, leading to a decrease in receptor synthesis rate. As a result, the number of receptor molecules on the membrane declines, which subsequently reduces iron uptake into the cell.

The degradation of transferrin mRNA is governed by hairpin structures (instability elements) located downstream of the coding sequences (Fig. 8.21). These instability elements bind a regulatory protein (aconitase) in its iron-free form. When complexed with this regulatory protein, the receptor mRNA remains stable and is efficiently translated. The Abundance of transferrin receptor molecules on the cell surface increases, leading to an elevated rate of iron influx. However, when intracellular iron levels are high, iron binds to the regulatory protein, diminishing its affinity for mRNA. The regulatory protein–mRNA complex dissociates, after which the mRNA is targeted by RNases and degraded. A reduction in mRNA levels leads to a lower rate of receptor synthesis; consequently, the number of receptor molecules on the cell surface decreases, and the rate of iron uptake into the cell drops accordingly.

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Fig. 8.21. Regulation of transferrin receptor synthesis

Regulation of Gene Expression by small interfering RNAs (siRNAs)

siRNAs are double-stranded molecules consisting of 21–28 NUCLEOTIDES, with two unpaired nucleotides at each end. siRNAs participate in mRNA degradation, thereby blocking the synthesis of the proteins encoded by them (Fig. 8.22). Upon the appearance of siRNA in the cell, it interacts with a helicase and a nuclease to form a complex. Utilizing the energy of ATP Hydrolysis, the helicase unwinds the siRNA strands. The RNA strand associated with the nuclease can then bind to a complementary region of a single-stranded mRNA, allowing the nuclease to cleave it. Subsequently, the partially fragmented mRNA is attacked by other cellular RNases, which cut it into even smaller fragments. Thus, The primary function of siRNA is to degrade RNAs that are complementary to one of its strands.

Fig. 8.22. Mechanism of siRNA action

siRNAs can be generated within the cell through the following mechanism: after binding to an mRNA strand, one of the siRNA strands can utilize a multi-enzyme complex possessing RNA-dependent RNA polymerase and RNA endonuclease activities to first synthesize the complementary mRNA strand and then cleave it, thereby producing "secondary" siRNAs (Fig. 8.23).

Fig. 8.23. Generation of siRNAs

Cells can also employ siRNAs to suppress the Replication of RNA-containing Viruses or to control the movement of Transposons throughout The Genome.

In medicine, siRNAs can be utilized to combat viral infections, and in Gene Therapy, to silence "disease-causing genes".

mRNA masking in eukaryotes

Under certain conditions, mRNA can become inaccessible to degradation, Translation initiation, or 3’-end polyadenylation—a process known as mRNA masking. Masking occurs when a so-called masking protein binds to a masking segment located in the 3’ untranslated region of the mRNA (Fig. 8.24). This binding inactivates the Functions of the mRNA along its entire length. Masking requires the presence of another, less specific RNA-binding protein, with which the mRNA forms a ribonucleoprotein complex. This process is reversible, and the reverse process is termed mRNA unmasking.

Fig. 8.24. Masking and unmasking of mRNA

mRNA masking and unmasking are characteristic of many biological processes, including gametogenesis, early embryonic development, and Cell Differentiation. For instance, oocytes store mRNA in a masked state, which becomes unmasked following Fertilization to drive Protein Synthesis during the Cytology/cytology/16.html">Early stages of embryonic development.