NEW YORK (Reuters Health) - Long trinucleotide repeats in Friedreich’s ataxia result in DNA replication stalling, according to a report in the March issue of Molecular and Cellular Biology.
“The case of Friedreich’s ataxia illustrates the role of a three-stranded DNA structure (triplex) in replication blockage, which eventually leads to repeat expansion and disease,” Dr. Sergei M. Mirkin from University of Illinois at Chicago, Chicago, Illinois told Reuters Health.
Dr. Mirkin and Dr. Maria M. Krasilnikova investigated the effects of Friedreich’s ataxia (GAA)n repeats of various lengths on DNA replication in a yeast plasmid model.
Normal-size repeats of (GAA)n did not influence DNA replication, the authors report, but replication progression was stalled beginning at (GAA) repeat lengths between 20 and 40.
“In humans, the normal sizes of (GAA)n repeats in the frataxin gene range from 7 to 34 U, the permutation sizes are 34 to 80 U, and the disease-size repeats exceed 100 U. Thus,” the investigators explain, “the repeat threshold length for replication blockade in yeast matches closely that for repeat expansion in humans.”
Upon cultivation of yeast, the researchers noted progressive accumulation of contractions and expansions of the repeat in its GAA orientation, pointing to a link between DNA replication stalling and an increase in the repeat length of (GAA)n.
“Replication of DNA repeats is error prone, occasionally leading to repeat expansions and disease,” Dr. Mirkin said. “Our data (together with others’, of course) explain the genetic phenomenon of anticipation (an increase in probability of transmission, severity, and onset of the disease as it passes through generations) in simple molecular terms. I believe that this knowledge could help establish molecular mechanisms of many other diseases, specifically those characterized by anticipation.”
“Understanding the mechanisms leading to repeat expansions might, in the long run, help develop therapeutics that could prevent further expansions and/or induce repeat contractions in affected individuals,” Dr. Mirkin said. “This certainly applies to many neurological disorders caused by repeat expansions.”
“While more progress was made in a yeast model system so far, we are actively extending these studies into mammalian/human cells,” Dr. Mirkin concluded. “Developing such systems could prove invaluable for studying basic mechanisms of repeat diseases and for the future search for potential therapeutics.”
Source: Mol Cell Biol 2004;24:2286-2295. [ Google search on this article ]
MeSH Headings:Microsatellite Repeats: Trinucleotide Repeats: Tandem Repeat SequencesCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.