Regulation of fragile sites expression in budding yeast by MEC1, RRM3 and hydroxyurea

Fragile sites are specific loci within the genome that exhibit increased tendencies for chromosome breakage. They are conserved among mammals and are also found in lower eukaryotes including yeast and fly. Many conditions, including mutations and exogenous factors, contribute to fragile site expression, but the nature of interaction among them remains elusive. Here, we investigated this by examining the combined effects of rrm3 Delta, mec1 and hydroxyurea (HU), three conditions that induce fragile sites, on expression of the replication slow zone (RSZ), a type of fragile site in budding yeast. Contrary to the expectation that each factor would contribute to fragile site expression in an independent manner, we show that rrm3 Delta and high concentrations of HU suppressed RSZ expression in mec1-4ts cells. Further analyses revealed that rrm3 Delta suppression occurs via promotion of Sml1 degradation, whereas HU suppresses RSZ via a premature commitment to inviability. Taken together, these observations demonstrate that: (1) the yeast genome contains different types of fragile site with regard to regulation of their expression, and (2) each fragile-site-inducing condition does not act independently, but can elicit a cellular response(s) that can paradoxically prevent the expression of a specific type(s) of fragile sites.