January 31, 2007 | David F. Coppedge

Cell Quality Control Runs a Tight Ship

Without the surveillance and rapid response of quality control, cells would collapse and die.  Here are some recently-published examples of nanoheroes in action.

  1. Plant checkpoints:  Picture a child watching the wonder of a seedling breaking through the soil into the light for the first time.  Within hours, the ghostly-white stem turns green, and a day later, leaves begin to appear.  Does he or she have any idea what is going on at a scale too small to see?  Not until that kid grows into a modern lab scientist with sophisticated equipment.  The transformation requires the coordinated transportation of key elements through specialized checkpoints, an international team reported in PNAS.1
        Without boring the reader with technical terms, what basically happens is this.  The underground seedling contains pre-chloroplast parts in readiness for the arrival into sunlight, but saves its energy by not allowing the light-gathering factories to assemble until it’s time.  “Chloroplasts need to import a large number of proteins from the cytosol because most are encoded in the nucleus,” they reported.  Once there, they have a double membrane to get through.  Specialized gates permit entry of the authenticated parts.  One particular light-sensitive part has its own unique gate.  The team decided to see what happened when they mutated one gene in the process.  The results were not pretty: the light-sensitive molecules accumulated outside the plastid because they couldn’t get into the factory.  “After a dark-to-light shift, this pigment operated as photosensitizer and caused rapid bleaching and cell death,” they found.  “Our results underscore the essential role of the substrate-dependent import pathway” that this protein depends on.  Maybe this error resembles a chemical spill outside a pharmaceutical plant, or pistons firing before they get into the engine.
  2. Now hear this:  In a surprise finding that might provide hope for the deaf, scientists publishing in PNAS reported that “Restoration of connexin26 protein level in the cochlea completely rescues hearing in a mouse model of human connexin30-linked deafness.”2  Two protein partners are needed for healthy hair-cell formation in the cochlea of the inner ear.  Mutations in one of them, connexin26, account for about half of all cases of inherited human deafness.  Usually, connexin26 and connexin30 join together to form gap junctions, but if one is mutated, deafness results.  The gap junctions are essential for cell-to-cell communication.  Surprisingly, connexin26 (Cx26) appears able to bridge the gap when connexin30 (Cx30) is missing; therefore, “up-regulation of Cx26 or slowing down its protein degradation might be a therapeutic strategy to prevent and treat deafness caused by Cx30 mutations.”
        The scientists suspected that these two isoforms of connexins regulate each other.  They also noted that this partnering occurs in the lens of the eye.  Losing one by mutation, therefore, affects the regulation of the partner.  On a hunch that one of the isoforms could compensate for the loss of the other if allowed to assemble, and could build functional gap junctions on its own, they tried up-regulating the remaining connexin.  To their surprise, hearing was completely restored in mice. 
  3. Bad translator triggers SOS:  We’ve talked about the DNA translation team a number of times (e.g., 12/28/2006, 07/26/2005, 06/09/2003, 04/29/2003).  The team of 20 aminoacyl-tRNA synthetases, as they are called, have rigid requirements.  “Mistranslation in bacterial and mammalian cells leads to production of statistical proteins that are, in turn, associated with specific cell or animal pathologies, including death of bacterial cells, apoptosis of mammalian cells in culture, and neurodegeneration in the mouse,” said Bacher and Schimmel in PNAS.3  “A major source of mistranslation comes from heritable defects in the editing activities of aminoacyl-tRNA synthetases.”  This is because the protein machines, which snap the right amino acid onto the appropriate transfer-RNA (tRNA), cannot perform their vital role in protein synthesis if broken.
        These researchers suspected that broken synthetases could also cause mutations.  They decided to test what happens when they caused an “editing defect” in one of them.  (These enzymes are usually able to proofread their own errors with a high degree of accuracy.)  The result, again, was not pretty: “A striking, statistically significant, enhancement of the mutation rate in aging bacteria was found.”  The bug was like flipping a fire alarm: “This enhancement comes from an increase in error-prone DNA repair through induction of the bacterial SOS response,” they explained.  “Thus, mistranslation, as caused by an editing-defective tRNA synthetase, can lead to heritable genetic changes that could, in principle, be linked to disease.”
        Another press release from Ohio State also discussed the neurological disease that can result from mistranslated proteins caused by mutated aminoacyl-tRNA synthetases.

1Pollman et al, “A plant porphyria related to defects in plastid import of protochlorophyllide oxidoreductase A,” Proceedings of the National Academy of Sciences USA, 10.1073/pnas.0610934104, published online before print January 29, 2007.
2Ahmad et al, “Restoration of connexin26 protein level in the cochlea completely rescues hearing in a mouse model of human connexin30-linked deafness,” Proceedings of the National Academy of Sciences USA, 10.1073/pnas.0606855104, published online before print January 16, 2007.
3Jamie M. Bacher and Paul Schimmel, “An editing-defective aminoacyl-tRNA synthetase is mutagenic in aging bacteria via the SOS response,” Proceedings of the National Academy of Sciences USA, 10.1073/pnas.0610835104, published online before print January 30, 2007.

Dear Darwinist, does this increase your faith that random accidents in working systems are going to make things better?  Is this a better way to build a plant, an ear, or a translation system?  If you think terrorism is the best way to build a civilization, reread the 12/14/2006 entry. 

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