Distinct DNA repair pathways cause genomic instability at alternative DNA structures

Area of Science:

• Genetics
• Molecular Biology
• Cancer Research

Background:

• Alternative DNA structures, such as Z-DNA, are implicated in mutagenesis and are found at mutation hotspots in human cancer genomes.
• The precise mechanisms by which these structures contribute to genomic instability are not fully understood.

Purpose of the Study:

• To investigate the mutagenic potential of Z-DNA in eukaryotic cells.
• To identify the DNA repair pathways involved in processing Z-DNA and maintaining genomic stability.

Main Methods:

• Utilized yeast and human cell systems to study Z-DNA mutagenicity.
• Employed biochemical assays to assess the binding of DNA repair complexes to Z-DNA sequences.
• Investigated the role of specific repair complexes (ERCC1-XPF and MSH2-MSH3) in Z-DNA-induced genetic instability.
• Performed molecular modeling to understand complex interactions with Z-DNA.

Main Results:

• Z-DNA was found to be mutagenic in both yeast and human cells.
• The nucleotide excision repair complex (ERCC1-XPF) and the mismatch repair complex (MSH2-MSH3) are essential for preventing genetic instability caused by Z-DNA.
• Both ERCC1-XPF and MSH2-MSH3 bind to Z-DNA sequences, with ERCC1-XPF recruitment dependent on MSH2-MSH3.
• ERCC1-XPF-dependent DNA strand breaks occur near Z-DNA regions in human cell extracts.

Conclusions:

• Z-DNA is a mutagenic DNA structure in eukaryotes.
• The ERCC1-XPF and MSH2-MSH3 repair complexes play a critical role in recognizing and processing Z-DNA, thereby preventing Z-DNA-induced genomic instability.
• These findings elucidate a novel mechanism of Z-DNA-mediated mutagenesis and genomic instability in human disease.