January 12, 2005 | David F. Coppedge

DNA Translators Cannot Tolerate Editor Layoffs

We’ve explained elsewhere about the family of molecular machines called aminoacyl-tRNA synthetases (see 05/26/2004 entry and its embedded links).  Their job is to associate each word of DNA code (codon) with its corresponding piece of a protein (amino acid).  In a very real sense, they translate the DNA code into the protein code.  One amazing capability of these machines is that they proofread their work.  They can differentiate between similar molecules, and edit out incorrect pieces inserted by mistake.  Scientists from Scripps Institute writing in PNAS1 thought they would watch what happened when they gave one of these translators a mutation that diminished this editing ability.  It wasn’t pretty:

The genetic code is established in aminoacylation reactions catalyzed by aminoacyl-tRNA synthetases.  Many aminoacyl-tRNA synthetases require an additional domain for editing, to correct errors made by the catalytic domain.  A nonfunctional editing domain results in an ambiguous genetic code, where a single codon is not translated as a specific amino acid but rather as a statistical distribution of amino acids.  Here, wide-ranging consequences of genetic code ambiguity in Escherichia coli were investigated with an editing-defective isoleucyl-tRNA synthetase.  Ambiguity retarded cell growth at most temperatures in rich and minimal media.  These growth rate differences were seen regardless of the carbon source.  Inclusion of an amino acid analogue that is misactivated (and not cleared) diminished growth rate by up to 100-fold relative to an isogenic strain with normal editing function.  Experiments with target-specific antibiotics for ribosomes, DNA replication, and cell wall biosynthesis, in conjunction with measurements of mutation frequencies, were consistent with global changes in protein function caused by errors of translation and not editing-induced mutational errors.  Thus, a single defective editing domain caused translationally generated global effects on protein functions that, in turn, provide powerful selective pressures for maintenance of editing by aminoacyl-tRNA synthetases.   (Emphasis added.)

In short, removing the editing created big problems.  The poor bacteria were stunted and vulnerable to malfunctions.  When the translator could not maintain high fidelity by editing out mistakes, crippled proteins were produced, and the organism became a sitting duck for the harsh realities of survival.
Update 01/26/2005: This paper generated a commentary in PNAS by Randall Hughes and Andrew Ellington of the University of Texas.2  They agreed that “over the long run, there has been and will continue to be tremendous selective pressure to maintain the current genetic code.”  But they surmise that, since not all the substituted amino acids produced fatalities, evolution might take advantage of them.  “Taking advantage of protein misfolding might at first seem to be an improbable event,” they admit, “but this phenomenon is conceptually similar to other ways in which organisms take evolutionary advantage of even inclement environments.”  Like citizens under siege scrounging for food, they envision a cell under stress with “a general need to explore a larger genetic space or a larger protein folding space or both.”  Maybe the cell has already planned for such things through experience.  “To the extent that organisms have encountered environmental stress intermittently over evolutionary time,” they write, “it may even be advantageous to establish some sort of regulatory feedback between stress and phenotypic exploration.”  In the end, though, they agree that the cell works hard to prevent such errors and possesses exquisite means to eliminate typos.  That means it will be difficult to find ways to change the genetic code in lab organisms: “simple substitutions will be an uphill battle.”


1Bacher, Crécy-Lagard and Schimmel, “Inhibited cell growth and protein functional changes from an editing-defective tRNA synthetase,” Proceedings of the National Academy of Sciences USA, 10.1073/pnas.0409064102, published online before print January 12, 2005.
2Randall A. Hughes and Andrew D. Ellington, “Mistakes in translation don’t translate into termination,” Proceedings of the National Academy of Sciences USA, February 1, 2005, vol. 102, no. 5, pp. 1273-1274.

Notice that they implied that natural selection had strong motivation to preserve the editing function of these machines.  They did not say natural selection had the ability to originate these machines.  That supports creation, not evolution.  Hughes and Ellington added nothing but speculation: namely, the Darwinian plot line that stress is good, because it forces organisms to evolve or perish.  But they only gave examples of mechanisms that are already in place to respond to stress.  They did not show how a mindless cell would think to itself, “Y’know, I really ought to come up with a disaster plan.”

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