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Yeast Study Implicates DNA Repair Method in Mutation

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A form of DNA repair known as break-induced replication (BIR) can ramp up the risk of mutation in the genome, according to a yeast study appearing online last night in PLoS Biology.

Using reporter assays in the budding yeast Saccharomyces cerevisiae, researchers from the US and Sweden looked at how often frameshift mutations occur in conjunction with BIR, a DNA repair method that occurs at double-stranded DNA breaks. Because it spurs replication that starts at these breaks, they explained, the repair method sometimes produces copies of the genome that are less accurate than those made during typical DNA replication.

Indeed, the current study hints that BIR can carry a mutagenic cost, with findings from S. cerevisiae suggesting that the mutation rate can be up to thousands of times higher when BIR is implemented than under typical DNA replication conditions.

"We think there are at least four changes to the replication machinery that might occur to create a perfect storm or synergy that make BIR repair so mutagenic," senior author Anna Malkova, a biology researcher at Indiana University-Purdue University Indianapolis, said in a statement. "Our findings strongly suggest that mutagenesis caused by BIR doesn't happen slowly, it occurs in surges — sudden bursts which may lead to cancer."

Malkova and her colleagues assessed frameshift mutations in S. cerevisiae strains containing an inducible double-stranded break system using a set of frameshift mutation reporters based on different alleles of the LYS2 gene, which affects yeast's ability to grow in certain types of media.

In the process, they found that the frameshift mutation rate associated with BIR in the yeast strains tested was between around 780 and 2,800 times higher than that found during conventional replication.

And, the researchers reported, BIR-related mutations weren't limited to sites around double-strand DNA breaks, but also cropped up thousands of bases away from these breaks.

When the researchers began exploring the genes and pathways involved in this process using yeast mutants lacking specific genes, they found evidence that the BIR repair method employs the same polymerase enzymes typically used for DNA replication. But, the team explained, far more nucleotides crowded around the replicating DNA during BIR than during normal DNA replication.

Their results also hint that part of the problem lies in errors that are introduced at replication forks during BIR that are never corrected.

In the future, the team intends to keep scrutinizing the process to try to learn more about the source of BIR-related mutations — a search that they hope might eventually yield new clues about adaptation, mutation, and disease.

"Overall, we propose that BIR is a novel source of mutagenesis that may contribute to disease genesis and evolution," Malkova and her co-authors wrote.

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