Accidental double-strand breaks (DSBs) of the chromosome that frequently arise during cell proliferation, occur at specific genomic locations known as fragile sites and cause genome instability. In budding yeast, inactivation of the DNA helicase Rrm3 induces DSBs at fork pause sites, thermal inactivation of the ATR homologue Mec1 induces DSBs at replication slow zones (RSZs) and exposure of checkpoint alleles of MEC1 to hydroxyurea (HU) induces chromosome breakage at yet-another set of fragile sites. Now, on page , Rita Cha and colleagues examine whether the different conditions that induce breakage at fragile sites in budding yeast interact. Unexpectedly, RRM3 deletion and high concentrations of HU both suppress RSZ expression in mec1 temperature-sensitive cells. Moreover, whereas rrm3D suppresses RSZ expression by promoting the degradation of the ribonucleotide reductase inhibitor Sml1, which regulates dNTP production, HU suppresses RSZ expression through premature commitment to inviability. These data indicate that the yeast genome (and presumably other eukaryotic genomes) contains fragile sites that differ in the regulation of their expression, and that fragile-site-inducing conditions can paradoxically prevent the expression of some types of fragile site, but induce the expression of others.
