Gross-chromosomal rearrangements are a hallmark of cancers and hereditary diseases. On the other hand, these events can trigger the generation of polymorphisms and lead to evolution. The driving force behind chromosomal rearrangements is DNA double strand breaks. A variety of factors can contribute to the generation of breaks in the genome. A paradoxical source of breaks is the sequence composition of the genomic DNA itself. Eukaryotic and prokaryotic genomes contain sequence motifs capable of adopting secondary structures often found to be potent inducers of double strand breaks culminating into rearrangements. These regions are therefore termed fragile sequence motifs.

A recently published study authored by Natalie Saini and colleagues in the lab of Kirill Lobachev (School of Biology), demonstrates that two particular types of fragile sequence motif, inverted repeats and triplex-forming repeats, increase mutation frequency in surrounding DNA regions. Interestingly, repeat-induced mutagenesis was found to spread large distances on either side flanking the break-point and requires the activity of an error-prone DNA polymerase. Remarkably, repair of the induced double-strand break via homologous recombination, a process previously thought to be error-free, also yields mutations and reconstitutes the repeats. This discovery is the first demonstration that inverted repeats and triplex-forming repeats provide a long-term source of DNA breakage and mutagenic repair. Consequently, secondary structure-forming repeats are a dual threat to genome stability due to their inherent potential to induce both rearrangements and mutations in the flanking DNA regions.

The study was published in Public Library of Science (PLoS) Genetics on 13 June 2013 and can be found at: http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1003551. Funding for this research was provided by grants from the NSF and NIH to Kirill Lobachev.