The Effect of Dysregulation of tRNA Genes and Translation Efficiency Mutations in Cancer and Neurodegeneration

the fidelity ANd efficieNcy of tRANslAtioN The two major steps of gene translation are transcription of the gene to mRNA molecules, and their translation to proteins by the ribosomes. The elongation part of translation includes the iterative decoding of the gene codons by the ribosome with the aid of tRNA molecules. Each codon is recognized by a set of tRNA molecules that are charged with the amino acid encoded by it (Alberts et al., 2002), and the translation time of a codon is usually positively correlated with the abundance of the tRNA molecules recognizing it. Thus, increasing expression levels of the tRNA molecules recognizing a codon, or replacing a codon with a different one recognized by tRNA molecules with higher expression levels, should usually have positive effect on its translation rate (Gustafsson et al., 2004; Tuller et al., 2010). Missense errors in translation occur at a rate of 1 per 10–10 (Ogle and Ramakrishnan, 2005; Kramer and Farabaugh, 2007), i.e., assuming average protein length of 400 codons, around 18% of the proteins contain at least one missense substitution. In addition, roughly 10–50% of random substitutions disrupt protein function, usually due to loss of folding mutations (Pakula and Sauer, 1989; Markiewicz et al., 1994; Guo et al., 2004; Bloom et al., 2006). It is known that the speed by which codons are translated can also affect the rate of missense translation errors, and thus the folding of the translated protein, resulting in misfolded toxic proteins (Akashi, 1994; Bloom et al., 2006; Zhou et al., 2009). Thus, the probability of missense translation errors of codons that are recognized by tRNA genes with lower concentrations is usually higher than in codons with higher concentrations, since in these cases with higher probability a wrong tRNA replaces the right one (Akashi, 1994; Zhou et al., 2009).