CSHL scientists clarify editing error underlying genetic neurodegenerati...(are called splice sites. Such sites are...)

Date:1/28/2009

are called splice sites. Such sites are composed of short sequences of RNA "letters" (called "bases"), which are referred to by single-letter molecular shorthands: A, U, G and C. The cell's RNA splicing machinery is correctly guided to the splice site at the beginning of an intron by one of its components, a small nuclear RNA called U1.

U1 recognizes this splice site by lining up against the target RNA and pairing a segment of its own RNA bases with the splice site's RNA bases following a set of rules: U pairs with A or G, and C pairs with G. U1's ability to recognize this splice site at the start of the intron is strongest when up to 11 bases are paired up.

When Krainer and postdoctoral researcher Xavier Roca, Ph.D., analyzed SpliceRack, a comprehensive database of all ~200,000 known, functional splice sites found at the beginning of every intron in human genes, they were surprised to find many of these sites that didn't appear to have the right sequence of RNA bases to match U1. Experimental testing of particular examples of these sites showed, however, that they were in fact recognized by U1 and effectively used. These "atypical" sites, in other words, could be spliced to make the correct messenger RNA, despite the apparent mismatch.

Atypical sites are recognized due to a shift in base-pairing

This raises the question: how does U1 manage to recognize such a diverse set of sequences, which include sequences that seem to be very poor matches to U1? The answer, Krainer and Roca have found, is explained in at least some cases by how U1 lines up with its target RNA.

"In the three decades since RNA splicing was discovered, scientists have believed that a functional match between U1 and its target RNA occurs only when the RNA bases in U1 and the target line up in a unique way," explains Roca. "We now find that this rule sometimes has exceptions."

The CSHL team has now demonstrated that U1 is more flexible
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Contact: Hema Bashyam bashyam@cshl.edu 516-367-6822 Cold Spring Harbor Laboratory Source:Eurekalert

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