title: ATR prohibits replication catastrophe by preventing global exhaustion of RPA.
abstract: ATR, activated by replication stress, protects replication forks locally and suppresses origin firing globally. Here, we show that these functions of ATR are mechanistically coupled. Although initially stable, stalled forks in ATR-deficient cells undergo nucleus-wide breakage after unscheduled origin firing generates an excess of single-stranded DNA that exhausts the nuclear pool of RPA. Partial reduction of RPA accelerated fork breakage, and forced elevation of RPA was sufficient to delay such "replication catastrophe" even in the absence of ATR activity. Conversely, unscheduled origin firing induced breakage of stalled forks even in cells with active ATR. Thus, ATR-mediated suppression of dormant origins shields active forks against irreversible breakage via preventing exhaustion of nuclear RPA. This study elucidates how replicating genomes avoid destabilizing DNA damage. Because cancer cells commonly feature intrinsically high replication stress, this study also provides a molecular rationale for their hypersensitivity to ATR inhibitors.
authors.affiliation: Chromosome Stability and Dynamics Group, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
authors.forename: Luis Ignacio
authors.initials: LI
authors.lastname: Toledo
authors.forename: Matthias
authors.initials: M
authors.lastname: Altmeyer
authors.forename: Maj-Britt
authors.initials: MB
authors.lastname: Rask
authors.forename: Claudia
authors.initials: C
authors.lastname: Lukas
authors.forename: Dorthe Helena
authors.initials: DH
authors.lastname: Larsen
authors.forename: Lou Klitgaard
authors.initials: LK
authors.lastname: Povlsen
authors.forename: Simon
authors.initials: S
authors.lastname: Bekker-Jensen
authors.forename: Niels
authors.initials: N
authors.lastname: Mailand
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.forename: Jiri
authors.initials: J
authors.lastname: Lukas
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004261:DNA Replication; D042822:Genomic Instability; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D018741:Replication Origin; D051716:Replication Protein A / Q000378:metabolism*
chemical_list: D002843:Chromatin; D047428:Protein Kinase Inhibitors; C497167:RPA1 protein, human; D051716:Replication Protein A; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins