Study in Nature Structural and Molecular Biology says this structure enables replication stalling.

Scientists at Tufts University have found that one particular DNA repeat not only stalls a cell’s replication process but also thwarts its capacity to repair and restart it. The team worked with the specific trinucleotide repeat disorder CGG, because it is associated with hereditary neurological disorders such as fragile X syndrome and FRAXE mental impairment.

Researchers found that with replication stalled, the unusual structure of CGG repeats makes them fail to react to important checkpoint proteins Mrc1 in yeast or claspin in humans. Both proteins work to repair replication malfunctions during the S phase of the cell cycle. As a consequence, chromosomes under-replicate, become fragile, and break.

“Our cells have evolved elaborate checkpoint mechanisms to detect replication blocks and trigger the instant restart of DNA replication there,” explains Sergei Mirkin, Ph.D., White Family Professor of Biology at Tufts’ School of Arts and Sciences. “Are the CGG repeats causing the checkpoints to fail?”

Past research from the team had shown that peculiar long DNA sequences named palindromes change the shape of the molecule from a double helix into a hairpin-like structure, stalling replication.

In the current study, the group 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.

The research is published in the January issue of Nature Structural and Molecular Biology.


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