Alternative DNA structure formation in the mutagenic human c-MYC promoter.
Mutation 'hotspot' regions in the genome are susceptible to genetic instability, implicating them in diseases. These hotspots are not random and often co-localize with DNA sequences potentially capable of adopting alternative DNA structures (non-B DNA, e.g. H-DNA and G4-DNA), which have been identified as endogenous sources of genomic instability. There are regions that contain overlapping sequences that may form more than one non-B DNA structure. The extent to which one structure impacts the formation/stability of another, within the sequence, is not fully understood. To address this issue, we investigated the folding preferences of oligonucleotides from a chromosomal breakpoint hotspot in the human c-MYC oncogene containing both potential G4-forming and H-DNA-forming elements. We characterized the structures formed in the presence of G4-DNA-stabilizing K+ ions or H-DNA-stabilizing Mg2+ ions using multiple techniques. We found that under conditions favorable for H-DNA formation, a stable intramolecular triplex DNA structure predominated; whereas, under K+-rich, G4-DNA-forming conditions, a plurality of unfolded and folded species were present. Thus, within a limited region containing sequences with the potential to adopt multiple structures, only one structure predominates under a given condition. The predominance of H-DNA implicates this structure in the instability associated with the human c-MYC oncogene.
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd. Austin, TX 78723, USA.
Imee Marie A
IMA
Del Mundo
Department of Chemistry and Biochemistry, Southwestern University, 1001 E University Ave, Georgetown, TX 78626, USA.
Maha
M
Zewail-Foote
Department of Chemistry and Biochemistry, Texas State University, 601 University Dr., San Marcos, TX 78666, USA.
Sean M
SM
Kerwin
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd. Austin, TX 78723, USA.
Karen M
KM
Vasquez
D019457:Chromosome Breakage / Q000187:drug effects; D004247:DNA / Q000737:chemistry* / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D054856:G-Quadruplexes / Q000187:drug effects; D042822:Genomic Instability / Q000187:drug effects; D006801:Humans; D009153:Mutagens / Q000633:toxicity; D009154:Mutation / Q000187:drug effects; D009690:Nucleic Acid Conformation / Q000187:drug effects*; D009841:Oligonucleotides / Q000737:chemistry* / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
C489427:MYC protein, human; D009153:Mutagens; D009841:Oligonucleotides; D016271:Proto-Oncogene Proteins c-myc; C051802:triplex DNA; D004247:DNA