The researchers found that replication of normal-size repeats proceeded without a hitch.
With larger-length sequences, however, the replication machinery got stuck and replication stalled. According to Mirkin, this temporary stoppage is probably caused by the formation of an unusual three-stranded DNA structure. He first discovered such odd DNA structures during his post-doctoral studies back in 1987, though at the time their significance was unclear.
"I was really delighted to finally find that they have a biological role," Mirkin said.
In their current study, Mirkin and Krasilnikova found that when replication stalled, the triplet repeat multiplied, creating longer and longer threads of DNA.
"It's like a car getting stuck in a pothole. You keep spinning the wheels to get out of the pothole, but the more the wheels spin, the more mileage you put on the car, the more repeating units you add to your DNA," Mirkin said.
The researchers also found that the aberrant lengthening of the sequence was more likely if replication began in one direction rather than the other, starting from the TTC strand rather than the GAA strand.
Mirkin and Krasilnikova believe their results apply to many other neurological diseases linked to lengthy repeats, including myotonic dystrophy, fragile X mental retardation and Huntington's disease.
"Different genes and different parts of those different genes are involved in these diseases. But there is one common feature: when the number of repetitive units is small, under 40, they are harmless. Over that threshold, the repeats multiply, expanding with each replication and causing rare, but very serious neurological disorders that worsen as the
Contact: Sharon Butler
University of Illinois at Chicago