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

¹ Department of Molecular Genetics, Biochemistry, and Microbiology and ² Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267
³ Department of Biology, Indiana University, Bloomington, IN 47405
⁴ Department of Microbiology, and Molecular Genetics, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103
⁵ Shriners Hospitals for Children, Cincinnati, OH 45229
⁶ Department of Pharmacology and Toxicology and the Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, NH 03755

Correspondence to Yolanda Sanchez: Yolanda.Sanchez{at}Dartmouth.Edu

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 dun1 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 chk1 dun1 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.

Abbreviations used in this paper: ARS, autonomously replicating sequence; dNTP, deoxyribonucleotide triphosphate; GCR, gross chromosomal rearrangement; HU, hydroxyurea; preRC, prereplication complex; RI, replication intermediate.

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Related In this Issue article

Early origins sound S phase alarm

Nicole LeBrasseur
J. Cell Biol. 2008 180: 1053. [Full Text] [PDF]

This article has been cited by other articles:

• Chen, Y., Caldwell, J. M., Pereira, E., Baker, R. W., Sanchez, Y. (2009). ATRMec1 Phosphorylation-independent Activation of Chk1 in Vivo. J. Biol. Chem. 284: 182-190 [Abstract] [Full Text]  
• LeBrasseur, N. (2008). Early origins sound S phase alarm. JCB 180: 1053-1053 [Full Text]  

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