Replication stress checkpoint signaling controls tRNA gene transcription.

In budding yeast, the transcriptional machinery at tRNA genes naturally interferes with replication in a way that can promote chromosome breakage. Here we show that a signaling module composed of core components of the replication stress checkpoint pathway represses this fork-pausing machinery in normally cycling and genotoxin-treated cells. Specifically, the sensor kinase Mec1, the signaling adaptor Mrc1 and the transducer kinase Rad53 relay signals that globally repress tRNA gene transcription during unchallenged proliferation and under conditions of replication stress. Repressive signaling in genotoxin-treated cells requires Rad53-dependent activation of a conserved repressor of tRNA gene transcription, Maf1. Cells lacking Maf1 are sensitive to replication stress under conditions of elevated tRNA gene transcription. We propose that checkpoint control of the fork-pausing activity of tRNA genes complements the repertoire of replisome-targeted mechanisms by which checkpoint proteins promote faithful DNA replication.