Discovery Of Link Between CGG Repeats In DNA And Neurological Disorders

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Discovery Of Link Between CGG Repeats In DNA And Neurological

Disorders

http://www.medicalnewstoday.com/articles/135048.php

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 F. Surka and

postdoctoral fellows A. Shishkin and 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.