Key Concepts of Section 10.4

• Most mRNAs are degraded as the result of the gradual shortening of the poly(A) tail (deadenylation) followed by exosome-mediated 3′→5′ digestion, or removal of the 5′ cap and digestion by a 5′→3′ exoribonuclease (see Figure 10-27).

• Eukaryotic mRNAs encoding proteins that are expressed in short bursts generally have repeated copies of an AU-rich sequence (AU-rich element) in their 3′ UTR. Specific proteins that bind to these elements also interact with a deadenylating enzyme complex and cytoplasmic exosomes, promoting rapid RNA degradation.

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  Translation can be repressed by micro-RNAs (miRNAs), which form imperfect hybrids with sequences in the 3′ untranslated region (UTR) of specific target mRNAs. mRNAs bound by several miRNAs are concentrated in P bodies in the cytoplasm, where they are degraded by decapping followed by digestion by the cytoplasmic exosome.

• The related phenomenon of RNA interference, which probably evolved as an early defense system against viruses and transposons, leads to rapid degradation of mRNAs that form perfect hybrids with short interfering RNAs (siRNAs).

• Both miRNAs and siRNAs contain 21–23 nucleotides, are generated from longer precursor molecules, and are bound by an Argonaute protein and assembled into a multiprotein RNA-induced silencing complex (RISC). RISC complexes either repress translation of target mRNAs and induce their localization to P bodies, where they are degraded (miRNAs), or cleave them (siRNAs), generating unprotected ends that are rapidly degraded by cytoplasmic exosomes and the 5′→3′ exonuclease XRN1 (see Figures 10-28 and 10-29).

• Cytoplasmic polyadenylation is required for the translation of mRNAs with a short poly(A) tail. Binding of a specific protein to regulatory elements in the 3′ UTRs represses translation of these mRNAs. Phosphorylation of this RNA-binding protein, induced by an external signal, leads to lengthening of the 3′ poly(A) tail and thus translation (see Figure 10-31).

• Binding of various proteins to regulatory elements in the 3′ or 5′ UTRs of mRNAs regulates the translation or degradation of many mRNAs in the cytoplasm.

• Translation of ferritin mRNA and degradation of transferrin receptor (TfR) mRNA are both regulated by the same iron-sensitive RNA-binding protein, IRE-BP. At low iron concentrations, this protein has an active conformation that binds to specific sequences that form stem-loops in the mRNAs, inhibiting ferritin mRNA translation and degradation of TfR mRNA (see Figure 10-33). This dual control precisely regulates the iron level within cells.

• Nonsense-mediated decay and other mRNA surveillance mechanisms prevent the translation of improperly processed mRNAs encoding abnormal proteins that might interfere with the functioning of the corresponding normal proteins.

• Many mRNAs are transported to specific subcellular locations by sequence-specific RNA-binding proteins that bind localization sequences usually found in the 3′ UTR. These RNA-binding proteins then associate, directly or via intermediary proteins, with motor proteins that carry large RNP particles, containing many mRNAs bearing the localization signals, on actin or microtubule fibers to specific locations in the cytoplasm.