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Papers In Press, published online ahead of print February 9, 2004
Department of Biochemistry, University of Oxford, Oxford OX1 3QU
Corresponding Author: nicholas.lakin{at}bioch.ox.ac.uk
The ataxia telangiectasia mutated (ATM) related kinase ATR is a central component of the cell cycle checkpoint machinery required to induce cell cycle arrest in response to DNA damage. Accumulating evidence suggests a role for ATR in signalling DNA damage during S-phase. Here we show that ATR is recruited to nuclear foci induced by replication fork stalling in a manner that is dependent on the single stranded binding protein replication protein A (RPA). ATR associates with chromatin in asynchronous cell cultures and we use a variety of approaches to examine the association of ATR with chromatin in the absence of agents that cause genotoxic stress. Under our experimental conditions, ATR exhibits a decreased affinity for chromatin in quiescent cells and cells synchronised at mitosis, but increases its affinity for chromatin as cells re-enter the cell cycle. Using centrifugal elutriation to obtain cells enriched at various stages of the cell cycle, we show that ATR associates with chromatin in a cell cycle dependent manner, specifically during S-phase. Cell cycle association of ATR with chromatin mirrors that of RPA in addition to claspin, a cell cycle checkpoint protein previously shown to be a component of the replication machinery. Furthermore, association of ATR with chromatin occurs in the absence of detectable DNA damage and cell cycle checkpoint activation. These data are consistent with a model whereby ATR is recruited to chromatin during the unperturbed cell cycle and points to a role of ATR in monitoring genome integrity during normal S-phase progression.
J. Biol. Chem, 10.1074/jbc.M314212200
Submitted on December 28, 2003
Revised on January 26, 2004
Accepted on February 9, 2004
Recruitment of the cell cycle checkpoint kinase ATR to chromatin during S-phase
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