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
Hlavní autoři: Toledo, Luis Ignacio, Altmeyer, Matthias, Rask, Maj-Britt, Lukas, Claudia, Larsen, Dorthe Helena, Povlsen, Lou Klitgaard, Bekker-Jensen, Simon, Mailand, Niels, Bartek, Jiri, Lukas, Jiri
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 21.11.2013
Témata:
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
ISSN:1097-4172, 1097-4172
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Shrnutí: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.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2013.10.043