Prevalent and Dynamic Binding of the Cell Cycle Checkpoint Kinase Rad53 to Gene Promoters

Replication of the genome must be coordinated with gene transcription and cellular metabolism. These processes are controlled in part by the Rad53 (CHEK2 in mammals) checkpoint kinase and the Mrc1 replisome component, especially following replication stress in the presence of limiting deoxyribonucleotides. We examined cell cycle regulated, genome-wide binding of Rad53 to chromatin. The kinase bound to sites of active DNA replication initiation and fork progression, but unexpectedly to the promoters of numerous genes (>20% of all genes) involved in many cellular functions. At some genes, Rad53 promoter binding correlated with changes in gene expression. Rad53 promoter binding to certain genes is influenced by sequence-specific transcription factors and less by checkpoint signaling. In checkpoint mutants, untimely activation of late-replicating origins reduces the transcription of nearby genes, with concomitant localization of Rad53 to their gene bodies. We suggest that the Rad53 checkpoint kinase coordinates genome-wide replication and transcription under stress conditions.