CGG repeats associated with DNA instability and chromosome fragility form structures that block DNA synthesis in vitro.
A large increase in the length of a CGG tandem array is associated with a number of triplet expansion diseases, including fragile X syndrome, the most common cause of heritable mental retardation in humans. Expansion results in the appearance of a fragile site on the X chromosome in the region of the CGG array. We show here that CGG repeats readily form a series of barriers to DNA synthesis in vitro. There barriers form only when the (CGG)n strand is used as the template, are K(+)-dependent, template concentration-independent, and involve hydrogen bonding between guanines. Chemical modification experiments suggest these blocks to DNA synthesis result from the formation of a series of intrastrand tetraplexes. A number of lines of evidence suggest that both triplet expansion and chromosome fragility are the result of replication defects. Our data are discussed in the light of such evidence.
D000079:Acetaldehyde / Q000031:analogs & derivatives; D000477:Alkylating Agents; D001483:Base Sequence; D043283:Chromosome Fragile Sites; D002873:Chromosome Fragility; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication / Q000235:genetics*; D006147:Guanine / Q000378:metabolism; D006860:Hydrogen Bonding; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis; D011188:Potassium / Q000502:physiology; D013463:Sulfuric Acid Esters; D013698:Templates, Genetic; D018911:Trinucleotide Repeats / Q000235:genetics*
D000477:Alkylating Agents; D009838:Oligodeoxyribonucleotides; D013463:Sulfuric Acid Esters; C038235:bromoacetaldehyde; D006147:Guanine; D004247:DNA; D000079:Acetaldehyde; C007482:dimethyl sulfate; D011188:Potassium