Figure 1226

Degradation of Prokaryotic mRNA

A) The mRNA being translated has a 5' end unprotected by ribosomes. An endonuclease (RNase E) cuts near the 5' end. B) The released fragment is then cut by exonuclease, starting at its 3' end. C) The mRNA is shortened and the severed segment is degraded.

Exonuclease

Special mechanisms detect and destroy defective mRNA molecules.

The stability of eukaryotic mRNA depends on the presence or absence of destabilizing sequences. Short-lived mRNA often contains an AU-rich sequence of about 50 bases (known as an ARE) in its 3'-UTR. The consensus for the ARE is multiple repeats of the 5 base sequence AUUUA (hence ARE = AUUUA repeat element). An ARE-binding protein recognizes the ARE and promotes deadenylation and degradation (Fig. 12.28).

Nonsense Mediated Decay of mRNA

Eukaryotic cells possess a special RNA surveillance mechanism that destroys mRNA molecules that contain premature stop codons. Such defective mRNA molecules may result from expression of genes with nonsense mutations, in which a codon that codes for an amino acid is mutated into a stop codon, also referred to as a nonsense codon. Consequently, the mechanism for destroying these mRNAs is known as nonsensemediated decay or NMD.

NMD plays a protective role in eukaryotic organisms that are heterozygotes with one functional allele and one allele carrying a nonsense mutation. Full expression of the nonsense allele would result in production of a truncated protein. Sometimes this is merely a waste of resources. However, many polypeptides form multi-subunit complexes (either with themselves or with other polypeptides). In this case, aberrant forms of the protein may still bind to the complex and interfere with normal function. Hence, some truncated proteins are actively dangerous. Degradation of mRNA carrying the nonsense allele prevents the synthesis of the aberrant truncated proteins and so protects heterozygotes from possible deleterious effects.

FIGURE 12.27 Degradation of Eukaryotic mRNA

A) The mRNA is shown with the poly (A) tail bound to poly (A)-binding protein (PABP). B) An exonuclease sequentially removes the poly (A) tail. C) A decapping protein (Dcp1) removes the cap. D) Degradation of the mRNA proceeds in the 5' to 3' direction due to exonuclease Xrn1.

FIGURE 12.27 Degradation of Eukaryotic mRNA

A) The mRNA is shown with the poly (A) tail bound to poly (A)-binding protein (PABP). B) An exonuclease sequentially removes the poly (A) tail. C) A decapping protein (Dcp1) removes the cap. D) Degradation of the mRNA proceeds in the 5' to 3' direction due to exonuclease Xrn1.

Despite its name, nonsense-mediated decay probably evolved to deal with defective mRNA that results from errors in the expression of normal genes rather than from inherited mutations. In particular, errors during the complex RNA splicing process that removes introns can lead to defective mRNA molecules. It is notable that nonsensemediated decay is only found in eukaryotes but not in prokaryotes where splicing is largely absent.

Defective mRNA with premature stop codons may result from several events:

I. Expression of a mutant gene with an internal nonsense mutation.

II. Errors during expression of normal genes that create nonsense mutations.

a. Errors during transcription that insert incorrect bases resulting in a premature stop codon.

b. Errors during splicing that alter the reading frame and so create in frame stop codons.

c. Errors during splicing that result in the retention of all or part of an intron whose sequence includes in frame stop codons.

FIGURE 12.28 ARE Sequence Facilitates Digestion of Eukaryotic mRNA

A) The structure of undegraded eukaryotic mRNA shows the AUUUA repeat sequence, the cap and the poly (A) tail. B) ARE-binding protein recognizes a repeated AUUUA sequence. C) Poly (A) ribonuclease degrades the poly (A) tail. D) Endonucleases sever the mRNA at multiple sites.

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