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Repeating yourself—the DNA danger

CellTweets #2
Date:
September 16, 2011 

Every cell in the body starts off with essentially the same genome, but sometimes the DNA sequence in a cell gets changed. Some of these changes are due to normal physiology (e.g. DNA is rearranged in immune cells to generate diversity in the adaptive immune system), but others are actual errors that occur when the DNA is copied during cell replication. Some mistakes are simple changes in one 'letter' or base, but others involve the introduction of long sequences in which short DNA "words" are repeated many times. Like a skipping CD (or an old school vinyl record), small areas of the genome are repeated over and over again and once it's copied in the DNA, all subsequent cellular offspring, have the repeated mistake. Sometimes these DNA expansions change the gene so much that they lead to a shutdown in the production of one or more proteins. But often the expansions lead to the production of abnormal proteins in which those repeated DNA words code for the stuttering repeat of a single amino acid in the protein (see protein-DNA or genetic code). These mutant proteins with repeated amino acids can cause human diseases called triplet repeat disorders. The most well-known example is Huntington's disease, which involves the dramatic expansion of the amino acid glutamine in the protein huntingtin. The single letter code for glutamine is Q, so these are often referred to as polyQ diseases. Rarer disorders such as oculopharyngeal muscular dystrophy (OPMD) have repeats of the amino acid alanine. Understanding how cells deal with these abnormal proteins would help us determine why the cells get sick and how we might treat or even cure these diseases.

A recent paper from Konopka and colleagues in the June 15, 2011, issue of MBoC looked at how budding yeast, a unicellular organism often used to study cellular physiology, responds to polyalanine expansion. What they found was that it depends on how many times the amino acid was repeated. Specifically, they were studying a protein with a normally small region of alanines (single letter code A) that binds to cellular messenger RNA (mRNA), the intermediate code between DNA and proteins. When they expanded these polyA regions, cells accumulated protein aggregates and died. They could reduce the toxicity by removing the part of the protein that binds to mRNA. This trick worked for repeats less than 17 but not for repeats bigger than 20 alanines. Together this means that different repeat lengths make the cells sick in different ways. Why the big difference between 17 and 20 ? Well that's the big question. Understanding how length results in toxicity and which toxicities can be treated will expose an Achilles heel in what is now a set of diseases that are untreatable and incurable.

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