ATR prohibits replication catastrophe by preventing global exhaustion of RPA
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 origi...
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| Vydáno v: | Cell Ročník 155; číslo 5; s. 1088 |
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| Hlavní autoři: | , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
| Vydáno: |
United States
21.11.2013
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| Témata: | |
| ISSN: | 1097-4172, 1097-4172 |
| On-line přístup: | Zjistit podrobnosti o přístupu |
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| 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. |
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| AbstractList | 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.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. 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. |
| Author | Rask, Maj-Britt Povlsen, Lou Klitgaard Mailand, Niels Lukas, Jiri Lukas, Claudia Bartek, Jiri Toledo, Luis Ignacio Larsen, Dorthe Helena Altmeyer, Matthias Bekker-Jensen, Simon |
| Author_xml | – sequence: 1 givenname: Luis Ignacio surname: Toledo fullname: Toledo, Luis Ignacio organization: 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 – sequence: 2 givenname: Matthias surname: Altmeyer fullname: Altmeyer, Matthias – sequence: 3 givenname: Maj-Britt surname: Rask fullname: Rask, Maj-Britt – sequence: 4 givenname: Claudia surname: Lukas fullname: Lukas, Claudia – sequence: 5 givenname: Dorthe Helena surname: Larsen fullname: Larsen, Dorthe Helena – sequence: 6 givenname: Lou Klitgaard surname: Povlsen fullname: Povlsen, Lou Klitgaard – sequence: 7 givenname: Simon surname: Bekker-Jensen fullname: Bekker-Jensen, Simon – sequence: 8 givenname: Niels surname: Mailand fullname: Mailand, Niels – sequence: 9 givenname: Jiri surname: Bartek fullname: Bartek, Jiri – sequence: 10 givenname: Jiri surname: Lukas fullname: Lukas, Jiri |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/24267891$$D View this record in MEDLINE/PubMed |
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| References | Cell. 2014 Jan 16;156(1-2):374 24267882 - Cell. 2013 Nov 21;155(5):979-80 |
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| Snippet | ATR, activated by replication stress, protects replication forks locally and suppresses origin firing globally. Here, we show that these functions of ATR are... |
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| SubjectTerms | Ataxia Telangiectasia Mutated Proteins - metabolism Cell Line, Tumor Chromatin - chemistry Chromatin - metabolism DNA Damage - drug effects DNA Replication Genomic Instability Humans Neoplasms - drug therapy Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use Replication Origin Replication Protein A - metabolism |
| Title | ATR prohibits replication catastrophe by preventing global exhaustion of RPA |
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