A new target of DNA instability: repeat expansions. (Genetics).

Potaman VN, Bissler JJ, Hashem VI, Oussatcheva EA, Lu L, Shlyakhtenko LS, et al. 2003. Unpaired structures in SCA10 [(ATTCT).sub.n]*[(AGAAT).sub.n] repeats. J Mol Biol 326:1095-1111.

Genes in normal individuals contain short lengths of trinucleotide repeats in which a combination of nucleotides, the building blocks of DNA, are repeated several times. Such "repeats" usually repeat themselves fewer than 30 times, but research has identified 18 human genetic diseases associated with expansion of the number of these repeats, sometimes into the thousands. Fragile X syndrome, myotonic dystrophy, and Huntington disease are a few of these devastating diseases, which become increasingly severe and have earlier onsets in successive generations, a process known as anticipation. Scientists have theorized that if the cause of the repeat expansion can be discovered, there is hope for preventing it from occurring.

NIEHS grantee Richard R. Sinden and colleagues at Texas A&M University recently discovered a unique repeat associated with spinocerebellar ataxia type 10 (SCA10), a disease characterized by seizures and lack of muscle control. The repeat is made up of 10 nucleotides in the sequence [(ATTCT).sub.n]n*[(AGAAT).sub.n]. Normally this sequence repeats 10-22 times. People with SCA10 may have as many as 4,500 copies of this sequence.

The researchers studied the structural properties of this repeat cloned in circular plasmids. The [(ATTCT).sub.n]*[(AGAAT).sub.n] sequence is unique among expanding repeat sequences in that it has a very high content of A+T base pairs. The high A+T content is a feature of DNA sequences that form unpaired structures known as DNA unwinding elements, or base unpairing regions. The Texas researchers demonstrated that the [(ATTCT).sub.n]*[(AGAAT).sub.n] repeat does indeed unpair, leaving the DNA strands accessible for interaction with other molecules and thereby acting as a false site of DNA replication. The researchers hypothesize that if [(ATTCT).sub.n]*[(AGAAT).sub.n] and other DNA repeats act as strong origins of replication, "then anomalous and fractious replication may lead to amplification and expansion."

Although it remains to be seen if repeats associated with other expansion-related diseases support incorrect DNA replication initiation, this finding gives researchers a new target on which to focus, and may lead to further discoveries on how to prevent and treat genetic disease.