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              Protein Synthesis                                                                           233

              X. TRANSLATIONAL ACCURACY                         mutations in tRNA genes, typically in the anticodon, that
                                                                allow them to recognize a misplaced stop codon or un-
              A. Types of Potential Errors                      intended frameshift. Suppressor tRNAs may be amino-
                                                                acylated according to the amino acid specificity of their
              Given the complexity of protein synthesis, there are many
                                                                parent sequence, so therefore they insert this amino acid
              steps at which mistakes can occur, and it is remarkable
                                                                into the polypeptide at the location of the mRNA aberra-
              that the error rate is as low as it is. The two principal
                                                                tion. Alternatively, they may be misacylated because of the
              categories of translational mistakes are missense errors,
                                                                change in the anticodon sequence. As long as the inserted
              in which one amino acid is substituted for another or a
                                                                amino acid is not detrimental to the synthesized protein, a
              stop codon is not recognized, and errors of processivity,
                                                                suppressor tRNA rescues the gene mutation. For example
              in which frameshifting or premature termination occur.
                                                                the E. coli su6 suppressor tRNA inserts leucine into the
                Missense errors can take place because of misacylation
                                                                growing polypeptide chain at the position of a premature
              of a tRNA by an AARS, resulting in insertion of an incor-
                                                                UAA stop codon.
              rect amino acid despite a correct codon–anticodon match.
                                                                  Missense suppressors simply substitute one amino acid
              This potential problem is counteracted by active editing
                                                                for another to correct a mutation in the mRNA. Trans-
              by AARSs (see earlier), which is critical for maintaining
                                                                fer RNAs that suppress +1 frameshifts typically contain
              translational accuracy. Errors can also occur at the level of
                                                                an extra base in the anticodon and read a four-nucleotide
              the codon–anticodon interaction, such that a noncognate
                                                                codon, thereby restoring the correct translational frame.
              AA–tRNA is selected at the ribosome, again resulting in
                                                                  Suppressor tRNAs are of particular interest as more ex-
              amino acid misincorporation. The relative abundance of
                                                                amples of the genetic basis for specific diseases are found.
              cognate vs. noncognate AA–tRNA affects the accuracy
                                                                In many cases, missense or nonsense mutations in genes
              of amino acid incorporation. In particular when the next
                                                                for essential proteins correlate with diseases such as can-
              amino acid specified by the mRNA is unavailable, the
                                                                cer, cystic fibrosis, and amyotropic lateral sclerosis (ALS).
              frequency of missense errors increases. A special case
                                                                In fact, mutations in the tumor suppressor gene p53 are the
              of incorrect AA–tRNA selection is that of stop codon
                                                                single greatest cause of human cancers. One particular p53
              readthrough, in which an amino acid is inserted where
                                                                hotspot is at codon 213, where nonsense mutations have
              the protein should actually be terminated. This type of er-
                                                                been identified in human colorectal, gastric, ovarian, and
              ror results in a carboxy-terminal extension (added to the
                                                                breast cancers. Suppressor tRNAs designed to selectively
              nascent protein) that continues until the ribosome reaches
                                                                rescue these mutations by reading through the premature
              the next stop signal.
                                                                termination codon could be effective therapeutic agents
                Frameshift mutations occur because of a nucleotide in-
                                                                in a gene therapy approach. Several challenges remain,
              sertion or deletion in a protein’s gene. Errors in reading
                                                                however—the suppressor tRNA must be introduced into
              frame also occur when the ribosome “slips” along the
                                                                the affected cells, must be transcribed at high enough lev-
              mRNA in such a way that the sequence is not read in
                                                                els to be effective, must also be aminoacylated at high
              triplets corresponding to the codons of the message, but
                                                                levels, and must not excessively read through stop codons
              the ribosome moves two or four nucleotides instead. These
                                                                that specify the normal termination of translation for
              “slips” are −1or +1 frameshifts, respectively. Fortunately
                                                                other genes. These are active areas of research in several
              the ribosome usually encounters a stop codon shortly after
                                                                laboratories.
              the frameshift; this minimizes the effect of the mutation.
              (Although frameshifting can be the unintended result of
              translational inaccuracy, “programmed” frameshifts also  C. Selenocysteine Insertion at UGA Codons
              take place in special situations. These produce alternate
                                                                The trace element selenium is present in a number
              polypeptides from a single mRNA.) Premature termina-
                                                                of proteins in the form of cotranslationally inserted
              tion of a protein can occur when a nucleotide substitution
                                                                selenocysteine (Sec). This insertion occurs when a unique
              produces a stop codon in the middle of the gene sequence.           Sec
                                                                selenocysteinyl–tRNA  recognizes an internal UGA
              The peptidyl–tRNA may also dissociate prematurely from
                                                                codon. Selenocysteine has therefore been called the “21st
              the ribosome before the stop codon is reached.
                                                                amino acid” and its insertion at a nucleotide triplet that is
                                                                normally a termination signal represents an expansion of
                                                                the genetic code.
              B. Suppressor tRNAs
                                                                  Insertion of selenocysteine requires several adaptations
              For several of these error scenarios, faithful translation of  of the translational machinery. First, tRNA Sec  is amino-
              the genetic message is accomplished through the action of  acylated with serine by seryl–tRNA synthetase. The ser-
              suppressor tRNAs. These are the result of advantageous  ine attached to this misacylated species is then converted
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