Biologists discover link between CGG repeats in DNA and neurological disorders

Jan 11, 2009

Researchers have long known that some repetitive DNA sequences can make human chromosomes "fragile," i.e. appearing constricted or even broken during cell divisions. Scientists at Tufts University have found that one such DNA repeat not only stalls the cell's replication process but also thwarts the cell's capacity to repair and restart it. The researchers focused on this CGG repeat because it is associated with hereditary neurological disorders such as fragile X syndrome and FRAXE mental impairment.

In a study to be published in the January 2009 issue of the journal Nature Structural and Molecular Biology, Sergei Mirkin, White Family Professor of Biology at Tufts' School of Arts and Sciences, along with graduate students Irina Voineagu and Christine F. Surka and postdoctoral fellows Alexander A. Shishkin and Maria M. Krasilnikova, explored the link between CGG repeats and replication delays. Mirkin's research was funded by the National Institutes of Health.

Effect of palindromes

Past research from Mirkin's lab had shown that peculiar long DNA sequences named palindromes change the shape of the molecule from a double helix into a hairpin-like structure and, as a result, stall replication. When this happens chromosomes can break during cell division.

For the new research, Mirkin and his team analyzed different cloned CGG repeats in a mammalian cell culture line called COS-1 and in budding yeast cells. The researchers found that short triplets do not cause any problems. When the repeats got longer, however, the replication machinery got jammed and stalled in both systems. Thus, replication stalling likely accounts for the chromosomal fragility. They believe that this stalling is due to the formation of a stable, hairpin-like DNA structure formed by long CGG repeats.

Abnormal structures disable cellular checkpoints

"Our cells have evolved elaborate 'checkpoint' mechanisms to detect replication blocks and trigger the instant 'restart' of DNA replication there," said Mirkin. "Are the CGG repeats causing the checkpoints to fail?"

With replication stalled, Mirkin and his research team found that the CGG repeats did not respond to the key checkpoint protein called Mrc1 in yeast or claspin in humans. Both proteins work to repair replication malfunctions during the S phase of the cell cycle. Apparently, the unusual structure of CGG repeats acts to escape the cellular checkpoints. As a consequence, chromosomes under-replicate, become fragile and break.

Source: Tufts University

Explore further: Researchers discover new mechanism of DNA repair

Related Stories

Study shows where damaged DNA goes for repair

May 03, 2015

A Tufts University study sheds new light on the process by which DNA repair occurs within the cell. In research published in the May 15 edition of the journal Genes & Development and available May 4 onli ...

Viral proteins may regulate human embryonic development

Apr 21, 2015

A fertilized human egg may seem like the ultimate blank slate. But within days of fertilization, the growing mass of cells activates not only human genes but also viral DNA lingering in the human genome from ...

Pennies reveal new insights on the nature of randomness

Mar 04, 2015

The concept of randomness appears across scientific disciplines, from materials science to molecular biology. Now, theoretical chemists at Princeton have challenged traditional interpretations of randomness ...

Vaccines from a reactor

Mar 02, 2015

In the event of an impending global flu pandemic, vaccine production could quickly reach its limits, as flu vaccines are still largely produced in embryonated chicken eggs. Udo Reichl, Director at the Max ...

Recommended for you

Researchers discover new mechanism of DNA repair

Jul 03, 2015

The DNA molecule is chemically unstable giving rise to DNA lesions of different nature. That is why DNA damage detection, signaling and repair, collectively known as the DNA damage response, are needed.

The math of shark skin

Jul 03, 2015

"Sharks are almost perfectly evolved animals. We can learn a lot from studying them," says Emory mathematician Alessandro Veneziani.

Cuban, US scientists bond over big sharks

Jul 03, 2015

Somewhere in the North Atlantic right now, a longfin mako shark—a cousin of the storied great white—is cruising around, oblivious to the yellow satellite tag on its dorsal fin.

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.