Figure 7–70 The competition between effectively decapping one end and removing the poly-A tail from the other so that both halves are rapidly degraded. The mRNAs that are destroyed in this way carry specific nucleotide sequences, often in the 3ʹ UTRs, that serve as recognition sequences for these endonucleases. This strategy makes it especially simple to tightly regulate the stability of these mRNAs by blocking or exposing the endonuclease site in response to extracellular signals. For example, the addition of iron to cells decreases the stability of the mRNA that encodes the receptor protein that binds the iron-transporting protein transferrin, causing less of this receptor to be made. This effect is mediated by the iron-sensitive RNA-binding protein aconitase. Aconitase can bind to the 3ʹ UTR of the transferrin receptor mRNA and increase receptor production by blocking endonucleolytic cleavage of the mRNA. On the addition of iron, aconitase is released from the mRNA, exposing the cleavage site and thereby decreasing the stability of the mRNA (Figure 7–71).
regulation of mrnA Stability involves p-bodies and Stress Granules
We saw in Chapters 3 and 6 that large aggregates of proteins and nucleic acids that work together are often held in proximity by loose, low-affinity connections (see Figure 3–36). In this way, they function as “organelles” even though they are not surrounded by membranes. Many of the events discussed in the previous mRNA translation and mRNA decay.
the same two features of an mrnA molecule—its 5ʹ cap and the 3ʹ poly-A decay (see figure 7–69). the deadenylase that shortens the poly-A tail in the 3ʹ-to5ʹ direction associates with the 5ʹ cap. As described in Chapter 6 (see figure 6–70), the translation initiation machinery also associates with both the 5ʹ cap and the poly-A tail. (Adapted from M. Gao et al., Mol. Cell 5:479–488, 2000. with permission from elsevier.)
Figure 7–71 Two post-translational controls mediated by iron. (A) During iron starvation, the binding of aconitase to the 5ʹ Utr of the ferritin mrnA blocks translation initiation; its binding to the 3ʹ Utr of the transferrin receptor mrnA blocks an endonuclease cleavage site and thereby stabilizes the mrnA.
(B) in response to an increase in iron concentration in the cytosol, a cell increases its synthesis of ferritin in order to bind the extra iron and decreases its synthesis of transferrin receptors in order to import less iron across the plasma membrane. Both responses are mediated by the same iron-responsive regulatory protein, aconitase, which recognizes common features in a stem-loop structure in the mrnAs encoding ferritin and the transferrin receptor. Aconitase dissociates from the mrnA when it binds iron. But because the transferrin receptor and ferritin are regulated by different types of mechanisms, their levels respond oppositely to iron concentrations even though they are regulated by the same iron-responsive regulatory protein.
section—including decapping and RNA degradation—take place in aggregates known as Processingor P-bodies, which are present in the cytosol (Figure 7–72).