Orchestration of the S-phase and DNA damage checkpoint pathways by replication forks from early origins.
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 dun1Delta 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 chk1Delta dun1Delta 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.
Caldwell
Julie M
JM
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Chen
Yinhuai
Y
Schollaert
Kaila L
KL
Theis
James F
JF
Babcock
George F
GF
Newlon
Carol S
CS
Sanchez
Yolanda
Y
D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D000071877:Checkpoint Kinase 1; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics*; D015966:Gene Expression Regulation, Fungal / Q000235:genetics; D018816:Genes, cdc / Q000502:physiology*; D042822:Genomic Instability / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D016196:S Phase / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
D018797:Cell Cycle Proteins; D016213:Cyclins; D029701:Saccharomyces cerevisiae Proteins; D011494:Protein Kinases; C104169:DUN1 protein, S cerevisiae; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; D018844:Cyclin-Dependent Kinases