Abstract
Alternative DNA structure-forming sequences can stimulate mutagenesis and are enriched at mutation hotspots in human cancer genomes, implicating them in disease etiology. However, the mechanisms involved are not well characterized. Here, we discover that Z-DNA is mutagenic in yeast as well as human cells, and that the nucleotide excision repair complex, Rad10-Rad1(ERCC1-XPF), and the mismatch repair complex, Msh2-Msh3, are required for Z-DNA-induced genetic instability in yeast and human cells. Both ERCC1-XPF and MSH2-MSH3 bind to Z-DNA-forming sequences, though ERCC1-XPF recruitment to Z-DNA is dependent on MSH2-MSH3. Moreover, ERCC1-XPF−dependent DNA strand-breaks occur near the Z-DNA-forming region in human cell extracts, and we model these interactions at the sub-molecular level. We propose a relationship in which these complexes recognize and process Z-DNA in eukaryotes, representing a mechanism of Z-DNA-induced genomic instability.
Highlights
Alternative DNA structure-forming sequences can stimulate mutagenesis and are enriched at mutation hotspots in human cancer genomes, implicating them in disease etiology
We show that the Rad10-Rad[1] (ERCC1-XPF) complex that acts in the nucleotide excision repair (NER) pathway, and the Msh2-Msh[3] (MSH2-MSH3) complex that acts in the mismatch repair (MMR) pathway, interact on Z-DNA and are required for Z-DNA-induced genetic instability in yeast and human cells
We chose a Z-DNA-forming CG14 repeat in this study, as we have demonstrated that it forms a Z-DNA structure that stimulates the formation of double-strand breaks (DSBs) and large deletions in mammalian cells, rather than forming small loops that can occur at simple repeats[1]
Summary
Alternative DNA structure-forming sequences can stimulate mutagenesis and are enriched at mutation hotspots in human cancer genomes, implicating them in disease etiology. We discover that Z-DNA is mutagenic in yeast as well as human cells, and that the nucleotide excision repair complex, Rad10-Rad1(ERCC1-XPF), and the mismatch repair complex, Msh2-Msh[3], are required for ZDNA-induced genetic instability in yeast and human cells. Both ERCC1-XPF and MSH2-MSH3 bind to Z-DNA-forming sequences, though ERCC1-XPF recruitment to Z-DNA is dependent on MSH2-MSH3. We propose a relationship between the ERCC1-XPF and MSH2-MSH3 complexes in recognizing and processing Z-DNA that is unique and distinct from their roles in canonical DNA repair pathways This relationship represents a mechanism of genomic instability, further implicating Z-DNA in translocationrelated diseases and cancer etiology
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