Naturally occurring H-DNA-forming sequences are mutagenic in mammalian cells.
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 approximately 20-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-myc gene 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.
Wang
Guliang
G
Department of Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, 1808 Park Road 1-C, Smithville, TX 78957, USA.
Vasquez
Karen M
KM
D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D004247:DNA / Q000737:chemistry* / Q000235:genetics*; D017353:Gene Deletion; D017930:Genes, Reporter / Q000235:genetics; D016153:Genes, Suppressor; D006801:Humans; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009690:Nucleic Acid Conformation; D010957:Plasmids / Q000235:genetics; D012343:RNA, Transfer / Q000235:genetics
C096275:supF tRNA; D004247:DNA; D012343:RNA, Transfer