A Mec1- and Rad53-dependent checkpoint controls late-firing origins of DNA replication

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Abstract
DNA replication in eukaryotic cells initiates from many replication origins1 which fire throughout the S phase of the cell cycle in a predictable pattern: some origins fire early, others late2. Little is known about how the initiation of DNA replication and the elongation of newly synthesized DNA strands are coordinated during S phase. Here we show that, in budding yeast, hydroxyurea, which blocks the progression of replication forks from early-firing origins, also inhibits the firing of late origins. These late origins are maintained in the initiation-competent prereplicative state for extended periods. The block to late origin firing is an active process and is defective in yeast with mutations in the rad53 and mec1 checkpoint genes, indicating that regulation of late origin firing may also be an important component of the ‘intra-S-phase’ checkpoint3 and may aid cell survival under adverse conditions.