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Papers In Press, published online ahead of print July 29, 2004
Center for Genome Research, Institute of Biosciences & Technology, Houston, TX 77030
Corresponding Author: rwells{at}ibt.tamu.edu
The genetic instabilities of (CCTG·CAGG)n tetranucleotide repeats were investigated to evaluate the molecular mechanisms responsible for the massive expansions found in myotonic dystrophy type 2 (DM2) patients. DM2 is caused by an expansion of the repeat from the normal allele of 26 to as many as 11,000 repeats. Genetic expansions and deletions were monitored in an African green monkey kidney cell culture system (COS-7 cells) as a function of the length (30, 114 or 200 repeats), orientation, or proximity of the repeat tracts to the origin (SV40) of replication. As found for CTG·CAG repeats related to DM1, the instabilities were greater for the longer tetranucleotide repeat tracts. Also, the expansions and deletions predominated when cloned in orientation II (CAGG on the leading strand template) rather than I and when cloned proximal rather than distal to the replication origin. Biochemical studies on synthetic d(CAGG)26 and d(CCTG)26 as models of unpaired regions of the replication fork revealed that d(CAGG)26 has a marked propensity to adopt a defined base paired hairpin structure whereas the complementary d(CCTG)26 lacks this capacity. The effect of orientation described above differs from all previous results with three triplet repeat sequences (TRS) (including CTG·CAG) which are also involved in the etiologies of other hereditary neurological diseases. However, similar to the TRS, the ability of one of the two strands to form a more stable folded structure, in our case the CAGG strand, explains this unorthodox “reversed” behavior.
J. Biol. Chem, 10.1074/jbc.M406415200
Submitted on June 9, 2004
Revised on July 21, 2004
Accepted on July 29, 2004
Hairpin structure-forming propensity of the (CCTG5CAGG) tetranucleotide repeats contributes to the genetic instability associated with myotonic dystrophy type 2
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