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Summary: Sequences with the capacity to adopt alternative DNA structures have been implicated in cancer etiology; however, the mechanisms are unclear. For example, H-DNA-forming sequences within oncogenes have been shown to stimulate genetic instability in mammals. Here, we report that H-DNA-forming sequences are enriched at translocation breakpoints in human cancer genomes, further implicating them in cancer etiology. H-DNA-induced mutations were suppressed in human cells deficient in the nucleotide excision repair nucleases, ERCC1-XPF and XPG, but were stimulated in cells deficient in FEN1, a replication-related endonuclease. Further, we found that these nucleases cleaved H-DNA conformations, and the interactions of modeled H-DNA with ERCC1-XPF, XPG, and FEN1 proteins were explored at the sub-molecular level. The results suggest mechanisms of genetic instability triggered by H-DNA through distinct structure-specific, cleavage-based replication-independent and replication-dependent pathways, providing critical evidence for a role of the DNA structure itself in the etiology of cancer and other human diseases. : DNA sequences that can adopt alternative structures, such as H-DNA, have been implicated in cancer etiology. Zhao et al. found that such sequences are enriched at translocation breakpoints in human cancer genomes and that repair- and replication-related nucleases cleave H-DNA in both error-free “replication-related” and mutagenic “replication-independent” mechanisms. Keywords: DNA structure, H-DNA, chromosome translocation, mutation hotspot, DNA repair, nuclease, structural simulation |
