Orchestration of the S-phase and DNA damage checkpoint pathways by replication forks from early origins

• Published in: The Journal of cell biology 2008-03, Vol.180 (6), p.1073-1086
• Main Authors: Caldwell, Julie M, Chen, Yinhuai, Schollaert, Kaila L, Theis, James F, Babcock, George F, Newlon, Carol S, Sanchez, Yolanda
• Format: Article
• Language: English
• Subjects: Cancer; Cell cycle; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Division - genetics; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cells; Cellular biology; Checkpoint Kinase 1; Cyclin-Dependent Kinases - genetics; Cyclin-Dependent Kinases - metabolism; Cyclins - genetics; Cyclins - metabolism; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - genetics; DNA replication; DNA Replication - genetics; Gene Expression Regulation, Fungal - genetics; Genes, cdc - physiology; Genomic Instability - genetics; Genomics; Intermediate uveitis; Interphase; Plasmids; Protein Kinases - genetics; Protein Kinases - metabolism; Protein-Serine-Threonine Kinases; Replication origin; S Phase - genetics; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Time Factors; Viability; Yeasts
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.200706009

The S-phase checkpoint activated at replication forks coordinates DNA replication when forks stall because of DNA damage or low deoxyribonucleotide triphosphate pools. We explore the involvement of replication forks in coordinating the S-phase checkpoint using dun1Δ cells that have a defect in the number of stalled forks formed from early origins and are dependent on the DNA damage Chk1p pathway for survival when replication is stalled. We show that providing additional origins activated in early S phase and establishing a paused fork at a replication fork pause site restores S-phase checkpoint signaling to chk1Δ dun1Δ cells and relieves the reliance on the DNA damage checkpoint pathway. Origin licensing and activation are controlled by the cyclin-Cdk complexes. Thus, oncogene-mediated deregulation of cyclins in the early stages of cancer development could contribute to genomic instability through a deficiency in the forks required to establish the S-phase checkpoint.