ATR Prohibits Replication Catastrophe by Preventing Global Exhaustion of RPA

TY - JOUR

T1 - ATR Prohibits Replication Catastrophe by Preventing Global Exhaustion of RPA

AU - Toledo Lazaro, Luis Ignacio

AU - Altmeyer, Matthias

AU - Rask, Maj-Britt

AU - Lukas, Claudia

AU - Larsen, Dorthe Helena

AU - Povlsen, Lou Klitgaard

AU - Bekker-Jensen, Simon

AU - Mailand, Niels

AU - Bartek, Jiri

AU - Lukas, Jiri

N1 - Copyright © 2013 Elsevier Inc. All rights reserved.

PY - 2013/11/21

Y1 - 2013/11/21

N2 - 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.

AB - 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.

U2 - 10.1016/j.cell.2013.10.043

DO - 10.1016/j.cell.2013.10.043

M3 - Journal article

C2 - 24267891

SN - 0092-8674

VL - 155

SP - 1088

EP - 1103

JO - Cell

JF - Cell

IS - 5

ER -