Hairpins are formed by the single DNA strands of the fragile X triplet repeats: structure and biological implications.
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.
Chen
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X
Center for Human Genome Studies, Los Alamos National Laboratory, NM 87545, USA.
Mariappan
S V
SV
Catasti
P
P
Ratliff
R
R
Moyzis
R K
RK
Laayoun
A
A
Smith
S S
SS
Bradbury
E M
EM
Gupta
G
G
D001483:Base Sequence; D004247:DNA / Q000737:chemistry* / Q000235:genetics*; D004277:DNA, Single-Stranded / Q000737:chemistry*; D004591:Electrophoresis, Polyacrylamide Gel; D005600:Fragile X Syndrome / Q000235:genetics*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis / Q000737:chemistry; D012091:Repetitive Sequences, Nucleic Acid
D004277:DNA, Single-Stranded; D009838:Oligodeoxyribonucleotides; D004247:DNA