Journal of the National Cancer Institute Advance Access published online on December 9, 2008
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn385
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© The Author 2008. Published by Oxford University Press.
DNA Structure-induced Genomic Instability In Vivo
Affiliations of authors: Department of Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Science Park–Research Division, Smithville, TX (GW, SC, JD, KMV); Buck Institute for Age Research, Novato, CA (JV)
Correspondence to: Karen M. Vasquez, PhD, 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 (e-mail: kvasquez{at}mdanderson.org).
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.
| CONTEXT AND CAVEATS Prior knowledge Nonrandom chromosomal rearrangements that originate from double-strand DNA breaks at genomic "hotspots" are known to occur in some types of cancer; however, how DNA structure is involved is unclear. Study design A transgenic mouse model using DNA sequences that form H-DNA, Z-DNA, and normal helical B-DNA structures. Contribution Chromosome breakage and rearrangements occurred in regions of H-DNA and Z-DNA but not in control B-DNA. Implications DNA structure may have a role in chromosome breakage and rearrangements. Limitations How these DNA structures might induce the chromosome rearrangements observed in human cancer and how they form in premalignant cells are still unresolved. From the Editors
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Manuscript received February 15, 2008; revised September 10, 2008; accepted September 24, 2008.
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