Repetitive DNA sequences, interspersed throughout the human genome, are capable of forming a wide variety of unusual DNA structures with simple and complex loopfolding patterns. The hairpin formed by the fragile X repeat, (CCG)_n, and the bipartite triplex formed by the Friedreich's ataxia repeat, (GAA)_n/(TTC)_n, show simple loopfolding. On the other hand, the doubly folded hairpin formed by the human centromeric repeat, (AATGG)_n, the hairpin G-quartet formed by (TTAGGG)_n at the 3 telomere overhang, and the hairpin G-quartet, and hairpin C^+â€¢C paired i-motif formed by the insulin minisatellite,\left( \beginarrayl \rm ACAG_4\rm TGTG_4\\ \rm TGTC_4\rm ACAC_4 \endarray \right)_n,show multiple and complex loopfolding. We have performed high resolution nuclear magnetic resonance (NMR) spectroscopy and in vitro replication to show that unique base-pairing and loopfolding render stability to these unusual structures under physiological conditions. The formation of such stable structures offers a mechanism of unwinding which is advantageous during transcription. For example, the formation of the hairpin G-quartet, and hairpin C^+â€¢C paired i-motif upstream of the insulin gene may facilitate transcription. These unusual DNA structures also provide unique â€˜protein recognition motifsâ€™ quite different from a Watsonâ€“Crick double helix. For example, the hairpin G-quartet formed by (TTAGGG)_n at the 3 telomere overhang is specifically recognized and stabilized by the human repair protein, Ku70/Ku80 hetero-dimer, which may be important in the stability of the telomere. However, the formation of the same unusual DNA structures during replication is likely to cause instability in the lengths of the DNA repeats. If the altered (generally expanded) length enhances the probability of the unusual structure during the next cycle of replication, it further increases the instability of the repeat causing a â€˜dynamic mutationâ€™. In fact, NMR and in vitro replication studies show that the longer the repeat length the higher is the probability of hairpin formation by the fragile X repeat, (CCG)_n. In addition, the hairpin of the fragile X repeat, upstream of the FMR-1 gene, is more susceptible to CpG methylation than its duplex thereby leading to methyl-directed suppression of transcription. Thus, the selective advantage of the unusual structures formed by the DNA repeats in the regulation of gene expression may be offset by the genomic instability caused by the same structures during replication. The repeat number is a critical parameter that helps maintain a balance between the advantage gained from an unusual structure during gene expression and the disadvantage posed by the same structure during replication.
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