Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 101, Issue 37, Pages 13448-13453Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0405116101
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Funding
- NCI NIH HHS [R01 CA093729, CA 93729] Funding Source: Medline
- NIEHS NIH HHS [ES 07784, P30 ES007784] Funding Source: Medline
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Naturally occurring DNA sequences can form noncanonical structures such as H-DNA, which are abundant and regulate the expression of several disease-linked genes. Here, we show that H-DNA-forming sequences are intrinsically mutagenic in mammalian cells. This finding suggests that DNA is a causative factor in mutagenesis and not just the end product. By using the endogenous H-DNA-forming sequence found in the human c-myc promoter, mutation frequencies in a reporter gene were increased approximate to20-fold over background in COS-7 cells. H-DNA-induced double-strand breaks (DSBs) were detected near the H-DNA locus. The structures of the mutants revealed microhomologies at the breakpoints, consistent with a nonhomologous end-joining repair of the DSBs. These results implicate H-DNA-induced DSBs in c-mycgene translocations in diseases such as Burkitt's lymphoma and t(12;15) BALB/c plasmacytomas, where most breakpoints are found near the H-DNA-forming site. Thus, our findings suggest that H-DNA is a source of genetic instability resulting from DSBs and demonstrate that naturally occurring DNA sequences are mutagenic in mammals, perhaps contributing to genetic evolution and disease.
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