DNA repeats in the human genome

Repetitive DNA sequences, interspersed throughout the human genome, are cap able of forming a wide variety of unusual DNA structures with simple and co mplex loopfolding patterns. The hairpin formed by the fragile X repeat, (CC G)(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 f olded hairpin formed by the human centromeric repeat, (AATGG)(n), the hairp in G-quartet formed by (TTAGGG)(n) at the 3' telomere overhang, and the hai rpin G-quartet, and hairpin C+. C paired i-motif formed by the insulin mini satellite, [GRAPHICS] show multiple and complex loopfolding. We have performed high resolution nu clear magnetic resonance (NMR) spectroscopy and in vitro replication to sho w that unique base-pairing and loopfolding render stability to these unusua l structures under physiological conditions. The formation of such stable s tructures offers a mechanism of unwinding which is advantageous during tran scription. For example, the formation of the hairpin G-quartet, and hairpin C+. C paired i-motif upstream of the insulin gene may facilitate transcrip tion. These unusual DNA structures also provide unique 'protein recognition motifs' quite different from a Watson-Crick double helix. For example, the hairpin G-quartet formed by (TTAGGG)(n) at the 3' telomere overhang is spe cifically recognized and stabilized by the human repair protein, Ku70/Ku80 hetero-dimer, which may be important in the stability of the telomere. Howe ver, the formation of the same unusual DNA structures during replication is likely to cause instability in the lengths of the DNA repeats. If the alte red (generally expanded) length enhances the probability of the unusual str ucture during the next cycle of replication, it further increases the insta bility of the repeat causing a 'dynamic mutation'. In fact, NMR and in vitr o 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 m ethyl-directed suppression of transcription. Thus, the selective advantage of the unusual structures formed by the DNA repeats in the regulation of ge ne expression may be offset by the genomic instability caused by the same s tructures during replication. The repeat number is a critical parameter tha t helps maintain a balance between the advantage gained from an unusual str ucture during gene expression and the disadvantage posed by the same struct ure during replication.