title: The level of origin firing inversely affects the rate of replication fork progression.
abstract: DNA damage slows DNA synthesis at replication forks; however, the mechanisms remain unclear. Cdc7 kinase is required for replication origin activation, is a target of the intra-S checkpoint, and is implicated in the response to replication fork stress. Remarkably, we found that replication forks proceed more rapidly in cells lacking Cdc7 function than in wild-type cells. We traced this effect to reduced origin firing, which results in fewer replication forks and a consequent decrease in Rad53 checkpoint signaling. Depletion of Orc1, which acts in origin firing differently than Cdc7, had similar effects as Cdc7 depletion, consistent with decreased origin firing being the source of these defects. In contrast, mec1-100 cells, which initiate excess origins and also are deficient in checkpoint activation, showed slower fork progression, suggesting the number of active forks influences their rate, perhaps as a result of competition for limiting factors.
authors: Molecular and Computational Biology Program, University of Southern California, Los Angeles, CA 90089, USA.
authors: Yuan
authors: Y
authors: Zhong
authors: Tittu
authors: T
authors: Nellimoottil
authors: Jared M
authors: JM
authors: Peace
authors: Simon R V
authors: SR
authors: Knott
authors: Sandra K
authors: SK
authors: Villwock
authors: Janis M
authors: JM
authors: Yee
authors: Jeffrey M
authors: JM
authors: Jancuska
authors: Sanket
authors: S
authors: Rege
authors: Marianne
authors: M
authors: Tecklenburg
authors: Robert A
authors: RA
authors: Sclafani
authors: Simon
authors: S
authors: Tavaré
authors: Oscar M
authors: OM
authors: Aparicio
mesh_terms: D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins / Q000378:metabolism; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D004261:DNA Replication; D004271:DNA, Fungal / Q000096:biosynthesis / Q000235:genetics; D051738:Origin Recognition Complex / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D018741:Replication Origin; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004271:DNA, Fungal; C497214:ORC1 protein, S cerevisiae; D051738:Origin Recognition Complex; D029701:Saccharomyces cerevisiae Proteins; C489404:CDC7 protein, S cerevisiae; D064447:Checkpoint Kinase 2; D017346:Protein Serine-Threonine Kinases; C067022:RAD53 protein, S cerevisiae
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