CSHL scientists clarify editing error underlying genetic neurodegenerati...(in its binding than previously thought. ...)

Date:1/28/2009

in its binding than previously thought. Instead of only lining up in a manner such that a particular base in U1 pairs with the first base of the target intron's RNA sequence that is, in the conventional way the scientists have found that U1 can shift itself down to the next base in the intron's RNA sequence if this new arrangement allows more of U1's RNA bases to pair up with bases in the intron, thus producing a stronger match.

This phenomenon, which Krainer calls "shifting of the base-pairing," can be explained in terms of locks and keys. If the many different splice sites are thought of as different locks, then U1 is the master key that can open them all. Some locks don't match well with the master key at first try. But it has now been shown that if the key is shifted a bit so that more of the individual "serrations" of the "key" match those of the "locks," the key will work perfectly well.

Implications for Disease

This ability of U1 to slide down just a single RNA base to recognize an atypical splice site might seem like a slight adjustment, but disrupting this phenomenon can have pathological consequences.

In the specific context of the gene mutation implicated in PCH, base-pair shifting explains why this mutation causes a severe disease. Krainer and Roca's results indicate that the correct splice site of this gene is normally recognized by the sliding mechanism and not in the conventional way, as scientists had previously believed. The mutation disrupts this recognition, resulting in an abnormally "edited" RNA molecule. The "message" from the gene that is carried by the wrongly edited RNA, therefore, is faulty. This can result, in young children, in the onset of PCH.

The CSHL team's findings also have implications for studies aimed at uncovering and characterizing new disease-causing mutations, according to Krainer. "We expect to more accurately identify and understand certain splicing mutations that
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Contact: Hema Bashyam bashyam@cshl.edu 516-367-6822 Cold Spring Harbor Laboratory Source:Eurekalert

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