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, especially following replication stress in the
presence of limiting deoxyribonucleotides. The S. cerevisiae Rad53 (CHEK2
in mammals) checkpoint kinase plays a major role in cellular responses to
DNA replication stress.  Cell-cycle-regulated, genome-wide
binding of Rad53 to chromatin was examined. Under replication stress, the
kinase bound to sites of active DNA replication initiation and fork
progression, but unexpectedly to the promoters of about 20% of genes
encoding proteins involved in multiple cellular functions. Rad53 promoter
binding correlated with changes in expression of a subset of genes. Rad53
promoter binding to certain genes was influenced by sequence-specific
transcription factors and less by checkpoint signaling. However, 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 replication
stress conditions.