Linking PCNA-dependent replication and ATR by human Claspin.
Recent studies in Xenopus have identified a new checkpoint protein called Claspin that is believed to transduce the checkpoint DNA damage signals to Chk1 kinase. Here we show that the human Claspin homolog is a chromatin bound protein either in the absence or in the presence of damaged DNA, independent of its association with ATR. Furthermore, we show that human Claspin is found in complex with PCNA, an essential component of the DNA replication machinery, and is released upon DNA replication arrest. Interfering with PCNA function by overexpression of p21 mutant, impaired in its interaction with Cdks but not with PCNA, leads to ATR-dependent Chk1 activation. These findings suggest that the dissociation of Claspin-PCNA could be part of the signal leading to Chk1 activation.
Brondello
Jean-Marc
JM
INSERM EMI 0229 Génotypes et Phénotypes Tumoraux CRLC Val d'Aurelle, 34298 Montpellier, Cedex 5, France. jmbrondello@valdorel.fnclcc.fr
Ducommun
Bernard
B
Fernandez
Anne
A
Lamb
Ned J
NJ
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000502:physiology*; D000071877:Checkpoint Kinase 1; D002843:Chromatin / Q000502:physiology*; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D018809:Proliferating Cell Nuclear Antigen / Q000502:physiology*; D011494:Protein Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D029867:Xenopus Proteins
D048868:Adaptor Proteins, Signal Transducing; C488158:CLSPN protein, human; D018797:Cell Cycle Proteins; D002843:Chromatin; D018809:Proliferating Cell Nuclear Antigen; D029867:Xenopus Proteins; D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605875:Chek1 protein, Xenopus; D017346:Protein Serine-Threonine Kinases