Excessive Triplet Repeats Stall DNA Replication

Researchers have found that the repeated triplet segments of DNA that characterize Friedreich's ataxia prevent successful DNA replication when the number of repeats is more than 40, possibly due to the formation of an unusual three-stranded DNA structure that halts the replication process.

Friedreich's ataxia is a rare inherited disease that causes progressive damage to the nervous system resulting in symptoms ranging from muscle weakness and speech problems to heart disease. The ataxia results from the degeneration of nerve tissue in the spinal cord and nerves that control muscle movement in the arms and legs. The spinal cord becomes thinner and nerve cells lose some of their myelin sheath.

In 1996, an international group of researchers identified the cause of Friedreich's ataxia as a defect in a gene located on chromosome 9. Because of the inherited abnormal code, a particular sequence of bases (GAA) is repeated too many times. Normally, the GAA sequence is repeated 7 to 22 times, but in people with Friedreich's ataxia it is repeated 800 to 1,000 times.

In the current study, investigators at the University of Illinois, Chicago (USA; www.uic.edu), cloned Friedreich's ataxia (GAA) in repeats of various lengths into Saccharymyces cerevisiae plasmids, and their effects on DNA replication were analyzed using two-dimensional electrophoresis of replication intermediates. They reported in the March 2004 issue of Molecular and Cellular Biology that segment repeats longer than 40 units prevented DNA replication while segment repeats less than 40 units long did not.

"For Friedreich's ataxia and other neurological diseases, when the number of repeats exceeds 40, the sequence becomes unstable. That means that as the sequence is passed from one generation to the next, it gets longer. The longer it gets, the more likely it will get still longer. And the longer it gets, the worse the disease,” explained senior author Dr. Sergei Mirkin, professor of biochemistry and molecular genetics at the University of Illinois. "Individuals can be carriers of relatively long stretches of nucleotide repeats, with no apparent clinical consequences. But then some as yet unknown event triggers the addition of an extra triplet or two, and the threshold is crossed. Once replication stalls, there is no way back.”




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