title: ATR activates the S-M checkpoint during unperturbed growth to ensure sufficient replication prior to mitotic onset.
abstract: Cells must accurately replicate and segregate their DNA once per cell cycle in order to successfully transmit genetic information. During S phase in the presence of agents that cause replication stress, ATR-dependent checkpoints regulate origin firing and the replication machinery as well as prevent untimely mitosis. Here, we investigate the role of ATR during unperturbed growth in vertebrate cells. In the absence of ATR, individual replication forks progress more slowly, and an increased number of replication origins are activated. These cells also enter mitosis early and divide more rapidly, culminating in chromosome bridges and laggards at anaphase, failed cytokinesis, and cell death. Interestingly, cell death can be rescued by prolonging mitosis with partial inhibition of the mitotic cyclin-dependent kinase 1. Our data indicate that one of the essential roles of ATR during normal growth is to minimize the level of unreplicated DNA before the onset of mitosis.
authors.affiliation: Genome Stability Laboratory, Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland, Galway, Ireland.
authors.forename: John Kenneth
authors.initials: JK
authors.lastname: Eykelenboom
authors.affiliation: Genome Stability Laboratory, Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland, Galway, Ireland.
authors.forename: Emma Christina
authors.initials: EC
authors.lastname: Harte
authors.affiliation: Genome Stability Laboratory, Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland, Galway, Ireland.
authors.forename: Lynn
authors.initials: L
authors.lastname: Canavan
authors.affiliation: Genome Stability Laboratory, Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland, Galway, Ireland.
authors.forename: Ana
authors.initials: A
authors.lastname: Pastor-Peidro
authors.affiliation: Genome Stability Laboratory, Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland, Galway, Ireland.
authors.forename: Irene
authors.initials: I
authors.lastname: Calvo-Asensio
authors.affiliation: Genome Stability Laboratory, Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland, Galway, Ireland.
authors.forename: Marta
authors.initials: M
authors.lastname: Llorens-Agost
authors.affiliation: Genome Stability Laboratory, Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland, Galway, Ireland. Electronic address: noel.lowndes@nuigalway.ie.
authors.forename: Noel Francis
authors.initials: NF
authors.lastname: Lowndes
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics*; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors; D016923:Cell Death / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation; D002645:Chickens; D002842:Chromatids / Q000235:genetics; D048749:Cytokinesis / Q000235:genetics; D004261:DNA Replication / Q000235:genetics*; D055786:Gene Knockout Techniques; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics*; D011804:Quinolines / Q000494:pharmacology; D018741:Replication Origin / Q000235:genetics; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D011804:Quinolines; C512984:RO 3306; D013844:Thiazoles; D064007:Ataxia Telangiectasia Mutated Proteins; D016203:CDC2 Protein Kinase