Cell division cycle protein 45 (Cdc45) is crucial for the initiation as well as the elongation process of eukaryotic DNA replication. Our findings suggested that the Cdc45 protein is ubiquitylated and degraded by the proteasome pathway in human cells. Firstly, the fate of Cdc45 protein after induction of terminal differentiation of cultured human cells was significantly decelerated by application of proteasomal inhibitors. Secondly, we identified various putative destruction boxes and one KEN-box in the amino acid sequence of vertebrate Cdc45, which indicate that Cdc45 seems to be a novel substrate of the anaphase promoting complex/cyclosome. Thus, the evidences for ubiquitylation of Cdc45 refer the first posttranslational modification of this essential replication factor. We also found, that the human Cdc45 protein was not cleaved during apoptosis of cultured cells. This is in accordance with reports demonstrating the absence of indiscriminative cleavage of replication proteins during the programmed cell death.