title: Cell cycle-dependent formation of Cdc45-Claspin complexes in human cells is compromized by UV-mediated DNA damage.
abstract: The replication factor Cdc45 has essential functions in the initiation and elongation steps of eukaryotic DNA replication and plays an important role in the intra-S-phase checkpoint. Its interactions with other replication proteins during the cell cycle and after intra-S-phase checkpoint activation are only partially characterized. In the present study, we show that the C terminal part of Cdc45 may mediate its interactions with Claspin. The interactions of human Cdc45 with the three replication factors Claspin, replication protein A and DNA polymerase δ are maximal during the S phase. Following UVC-induced DNA damage, Cdc45-Claspin complex formation is reduced, whereas the binding of Cdc45 to replication protein A is not affected. We also show that treatment of cells with UCN-01 and phosphatidylinositol 3-kinase-like kinase inhibitors does not rescue the UV-induced destabilization of Cdc45-Claspin interactions, suggesting that the loss of the interaction between Cdc45 and Claspin occurs upstream of ataxia telangiectasia and Rad 3-related activation in the intra-S-phase checkpoint.
authors.affiliation: Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, Ireland.
authors.forename: Ronan
authors.initials: R
authors.lastname: Broderick
authors.forename: Michael D
authors.initials: MD
authors.lastname: Rainey
authors.forename: Corrado
authors.initials: C
authors.lastname: Santocanale
authors.forename: Heinz P
authors.initials: HP
authors.lastname: Nasheuer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004249:DNA Damage / Q000235:genetics / Q000528:radiation effects; D004261:DNA Replication / Q000235:genetics / Q000528:radiation effects; D006801:Humans
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C113571:CDC45 protein, human; C488158:CLSPN protein, human; D018797:Cell Cycle Proteins
keywords: Cdc45; DNA damage response; DNA replication; claspin; intra-S-phase checkpoint