ATR prohibits replication catastrophe by preventing global exhaustion of RPA

Cell. 2013 Nov 21;155(5):1088-103. doi: 10.1016/j.cell.2013.10.043.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*


  • Chromatin
  • Protein Kinase Inhibitors
  • RPA1 protein, human
  • Replication Protein A
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins