Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Faulty DNA replication linked to neurological diseases

05.03.2004


Lengthy sequences of DNA -- with their component triplet of nucleotides repeated hundreds, even thousands of times -- are known to be abnormal, causing rare but devastating neurological diseases. But how does the DNA get this way? How does it go haywire, multiplying out of control?



In the current issue of Molecular and Cellular Biology, Sergei Mirkin, professor of biochemistry and molecular genetics at the University of Illinois at Chicago College of Medicine, explains the mechanism, providing an important clue to the origin of these diseases.

Mirkin and Maria Krasilnikova, a research assistant professor in his lab, studied the sequence of a simple repeat of three nucleotides responsible for Friedreich’s ataxia, the most commonly inherited form of ataxias, which causes progressive damage to the nervous system, resulting in symptoms ranging from muscle weakness and speech problems to heart disease.


The DNA triplet that repeats in Friedreich’s ataxia is a guanine and two adenines (GAA) on one DNA strand and the complementary two thymines and a cytosine (TTC) on the opposite strand.

Earlier research had shown that up to 40 repeats of this nucleotide triplet do not cause any symptoms. The DNA is inherited as is, an odd but harmless pattern passed down from one generation to the next.

The problems begin when the repeats exceed 40.

"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," Mirkin said. "Basically, even if you are more or less okay, there is a probability that your kids will be sick and a still higher probability that your grandkids will be even sicker."

To study how and why the inherited sequence expands so rapidly, the scientists watched the replication of different lengths of the triplet repeat sequence, using a simple unicellular organism, yeast, as a convenient model. While yeast is far more primitive than humans, its mechanism of DNA replication is remarkably similar.

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 length of the repeats grows," Mirkin said.

"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," Mirkin said. "Once replication stalls, there is no way back."

Mirkin hypothesizes that the triggering event might be a switch in orientation, "but the million dollar question is what causes that switch."


The study was funded by the National Institute of General Medical Sciences, one of the National Institutes of Health.

Sharon Butler | UIC
Further information:
http://tigger.uic.edu/htbin/cgiwrap/bin/newsbureau/cgi-bin/index.cgi?from=Releases&to=Release&id=723&frommain=1
http://www.uic.edu

More articles from Life Sciences:

nachricht Molecular evolution: How the building blocks of life may form in space
26.04.2018 | American Institute of Physics

nachricht Multifunctional bacterial microswimmer able to deliver cargo and destroy itself
26.04.2018 | Max-Planck-Institut für Intelligente Systeme

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Why we need erasable MRI scans

New technology could allow an MRI contrast agent to 'blink off,' helping doctors diagnose disease

Magnetic resonance imaging, or MRI, is a widely used medical tool for taking pictures of the insides of our body. One way to make MRI scans easier to read is...

Im Focus: BAM@Hannover Messe: innovative 3D printing method for space flight

At the Hannover Messe 2018, the Bundesanstalt für Materialforschung und-prüfung (BAM) will show how, in the future, astronauts could produce their own tools or spare parts in zero gravity using 3D printing. This will reduce, weight and transport costs for space missions. Visitors can experience the innovative additive manufacturing process live at the fair.

Powder-based additive manufacturing in zero gravity is the name of the project in which a component is produced by applying metallic powder layers and then...

Im Focus: Molecules Brilliantly Illuminated

Physicists at the Laboratory for Attosecond Physics, which is jointly run by Ludwig-Maximilians-Universität and the Max Planck Institute of Quantum Optics, have developed a high-power laser system that generates ultrashort pulses of light covering a large share of the mid-infrared spectrum. The researchers envisage a wide range of applications for the technology – in the early diagnosis of cancer, for instance.

Molecules are the building blocks of life. Like all other organisms, we are made of them. They control our biorhythm, and they can also reflect our state of...

Im Focus: Spider silk key to new bone-fixing composite

University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.

Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.

Im Focus: Writing and deleting magnets with lasers

Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.

Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

IWOLIA: A conference bringing together German Industrie 4.0 and French Industrie du Futur

09.04.2018 | Event News

 
Latest News

World's smallest optical implantable biodevice

26.04.2018 | Power and Electrical Engineering

Molecular evolution: How the building blocks of life may form in space

26.04.2018 | Life Sciences

First Li-Fi-product with technology from Fraunhofer HHI launched in Japan

26.04.2018 | Power and Electrical Engineering

VideoLinks
Science & Research
Overview of more VideoLinks >>>