Open AccessHairpins are formed by the single DNA strands of the fragile X triplet repeats: structure and biological implications.
Author(s) -
Xian Chen,
S. V. Santhana Mariappan,
P. Catasti,
Robert L. Ratliff,
Robert K. Moyzis,
Ali Laayoun,
Steven S. Smith,
E. M. Bradbury,
Goutam Gupta
Publication year - 1995
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.92.11.5199
Subject(s) - cpg site , dna , heavy strand , duplex (building) , cytosine , chemistry , biology , biophysics , dna methylation , crystallography , microbiology and biotechnology , gene , genetics , rna , transfer rna , gene expression
Inordinate expansion and hypermethylation of the fragile X DNA triplet repeat, (GGC)n.(GCC)n, are correlated with the ability of the individual G- and C-rich single strands to form hairpin structures. Two-dimensional NMR and gel electrophoresis studies show that both the G- and C-rich single strands form hairpins under physiological conditions. This propensity of hairpin formation is more pronounced for the C-rich strand than for the G-rich strand. This observation suggests that the C-rich strand is more likely to form hairpin or "slippage" structure and show asymmetric strand expansion during replication. NMR data also show that the hairpins formed by the C-rich strands fold in such a way that the cytosine at the CpG step of the stem is C.C paired. The presence of a C.C mismatch at the CpG site generates local flexibility, thereby providing analogs of the transition to the methyltransferase. In other words, the hairpins of the C-rich strand act as better substrates for the human methyltransferase than the Watson-Crick duplex or the G-rich strand. Therefore, hairpin formation could account for the specific methylation of the CpG island in the fragile X repeat that occurs during inactivation of the FMR1 gene during the onset of the disease.