Dec. 22, 1997 Scientists at the University of Illinois at Chicago have found an important molecular clue to genetic diseases caused by expansions of repeated DNA segments.
They have shown that the lengths of the segments and the status of protein synthesis in a cell affect their replication. Researchers found that when the number of repeated segments exceeded a threshold, abnormal replication occurred. Their discovery could eventually set the stage for finding possible ways to block DNA mutations that result in disease.
The findings of the UIC research team, led by Sergei Mirkin, associate professor of molecular genetics, were published in the November issue of the journal Nature Genetics. The research was supported by grants from the National Science Foundation and the Council for Tobacco Research.
Individuals affected by disease carry hundreds, sometimes thousands of repeats of certain trinucleotides, while normal individuals carry only about five to 30 repeats. As a result of this expansion, the affected human genes do not function, resulting in disease. More than a dozen human disorders -- including a common form of mental retardation, Huntington's disease, myotonic dystrophy and several hereditary neurological diseases (ataxias) -- are now attributed to the expansion of repeats of certain trinucleotides in different human genes.
Mirkin and his colleagues, genetics postdoctoral fellow George Samadashwily and genetics graduate student Gordana Raca, analyzed the effects of various lengths of the trinucleotide repeats (CGG)n/(CCG)n and (CTG)n/(CAG)n on the replication of plasmids (small rings of DNA) in bacterial cells. They cloned long stretches of the trinucleotide repeats and used a sophisticated technique called two-dimensional gel electrophoresis to detect intermediate steps of DNA replication.
They found that the replication process of the repeated DNA segments is abnormal. When the number of uninterrupted repeats exceeded a critical threshold -- 30 to 50 repeats -- the replication process is temporarily stalled by the lengthy repeated segments. And, they found the greater the number of repeats above that threshold, the longer the stall, possibly resulting in an abnormal number of repeated segments being produced.
"Replication of the repeated segments took as much as ten times longer than it should have," says Mirkin. "We hypothesize that the abnormal expansion of the repeated segments occurs at this stalling point. "It's as if a car hits a large hole in the road, gets stuck and has to spin its wheels extensively to get out."
Mirkin adds that the mechanism that causes this replication blockage and subsequent expansion is not known yet. "Once that is understood, we can try to develop ways to bypass that roadblock and make the replication process go smoothly and thus avoid diseases," says Mirkin.
Mirkin sees significant future implications for this line of research. "We would expect to see many more diseases explained by this abnormal DNA replication process. We believe this expansion may occur in many other DNA repeats that are seen in many other diseases such as diabetes and epilepsy. In a sense, genetic diseases are a side product of the complexity of the DNA replication process, where genetic alterations almost inevitably occur."
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