DNA structure-induced genomic instability in vivo.
Noncanonical DNA structures are postulated to be responsible for some breakpoint hotspots that occur frequently in cancers. We developed a novel mouse model system using the naturally occurring H-DNA structure that deviate from the familiar right-handed helical B form found at the breakage hotspot in the human c-MYC promoter and a Z-DNA-forming CG repeat to test this idea directly. Large-scale chromosomal deletions and/or translocations occurred in 5 (7.7%, 95% confidence interval [CI] = 3.7% to 12.8%) of the 65 mice carrying the H-DNA-forming sequences and in 7 (6.6%, 95% CI = 3.8% to 11.6%) of the 106 mice carrying the Z-DNA-forming sequences, but in 0 of the 63 control mice (P = .042 and P = .035, respectively, two-sided test). Thus, the DNA structure itself can introduce instability in a mammalian genome.
Wang
Guliang
G
Department of Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, 1808 Park Rd 1C, PO Box 389, Smithville, TX 78957, USA.
Carbajal
Steve
S
Vijg
Jan
J
DiGiovanni
John
J
Vasquez
Karen M
KM
D000818:Animals; D002869:Chromosome Aberrations; D019457:Chromosome Breakage; D002872:Chromosome Deletion; D007446:Chromosome Inversion; D004247:DNA; D004273:DNA, Neoplasm; D043542:DNA, Z-Form; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D016133:Polymerase Chain Reaction; D014178:Translocation, Genetic
D004273:DNA, Neoplasm; D043542:DNA, Z-Form; C051802:triplex DNA; D004247:DNA