Genetic network interactions among replication, repair and nuclear pore deficiencies in yeast

The yeast RAD27 gene encodes a functional homolog of the mammalian FEN I protein, a structure-specific endo/exonuclease which plays an important role in DNA replication and repair. Previous genetic interaction studies, including a synthetic genetic array (SGA) analysis, showed that the survival of rad27 Delta cells requires several DNA metabolic processes, in particular those mediated by all members of the Rad52-dependent recombinational repair pathway. Here, we report the results of our SGA analysis of the collection of non-essential yeast genes against the rad27 Delta mutation, which resulted in the identification of a novel synthetic lethal interaction conferred by mutations affecting the Nup84 nuclear pore subcomplex (nup133 Delta, nup120 Delta and nup84 Delta). Additional screens showed that all RaJ52 group genes are required for the survival of the nup133 Delta and nup120 Delta mutants, which are defective in nuclear pore distribution and mRNA export, but not of the nup133 Delta N mutant, which is solely defective in pore distribution. This requirement for the DNA double-strand break (DSB) repair pathway is consistent with the observation that, like rad27 Delta, the nup133 Delta, nup120 Delta and nup84 Delta mutants are sensitive to methyl methanesulfonate (MMS). Furthermore, nup133 Delta cells exhibit an increased number of spontaneous DNA repair foci containing Rad52. Altogether, these data suggest that the pathological interactions between the rad27 Delta and specific nup Delta mutations result from the accumulation of unrepaired DNA damages. (c) 2004 Elsevier B.V. All rights reserved.