title: Turning the replication checkpoint on and off.
abstract: The replication checkpoint monitors the progress of DNA replication forks during S phase, and delays the firing of later replication origins when active replication forks are stalled due to collisions with damaged or abnormally structured DNA. Key components of the replication checkpoint pathway are the apical protein kinase, ATR, and its downstream target kinase, Chk1. Defects in either ATR or Chk1 function result in loss of DNA replication fidelity and cell viability, even in the absence of extrinsic genotoxic stress. Moreover, several clinically important antitumor agents, such as the camptothecins (CPTs), exert their antitumor effects by interfering with DNA replication, and hence the therapeutic response to these drugs is intimately related to signaling through the replication checkpoint. A recent report from this laboratory adds a new facet to the regulatory mechanisms that control the function and duration of checkpoint signaling through the ATR-Chk1 pathway. The results indicate that replication stress induced by a variety of agents, including CPT and deep hypoxia, triggers the ubiquitin-dependent degradation of the checkpoint kinase Chk1 in both normal and transformed human cells. This review provides an overview of the study's major findings, together with their implications for both replication checkpoint function and tumor responsiveness to CPT and related anticancer drugs.
authors.affiliation: Molecular and Cellular Biology, The Salk Institute, La Jolla, California, USA.
authors.forename: You-Wei
authors.initials: YW
authors.lastname: Zhang
authors.forename: Tony
authors.initials: T
authors.lastname: Hunter
authors.forename: Robert T
authors.initials: RT
authors.lastname: Abraham
mesh_terms: D000071877:Checkpoint Kinase 1; D004261:DNA Replication / Q000502:physiology*; D006801:Humans; D011494:Protein Kinases / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism
chemical_list: D044843:SKP Cullin F-Box Protein Ligases; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1