Unscheduled expression of CDC25B in S-phase leads to replicative stress and DNA damage.
BACKGROUND
CDC25B phosphatase is a cell cycle regulator that plays a critical role in checkpoint control. Up-regulation of CDC25B expression has been documented in a variety of human cancers, however, the relationships with the alteration of the molecular mechanisms that lead to oncogenesis still remain unclear. To address this issue we have investigated, in model cell lines, the consequences of unscheduled and elevated CDC25B levels.


RESULTS
We report that increased CDC25B expression leads to DNA damage in the absence of genotoxic treatment. H2AX phosphorylation is detected in S-phase cells and requires active replication. We also report that CDC25B expression impairs DNA replication and results in an increased recruitment of the CDC45 replication factor onto chromatin. Finally, we observed chromosomal aberrations that are also enhanced upon CDC25B expression.


CONCLUSIONS
Overall, our results demonstrate that a moderate and unscheduled increase in CDC25B level, as observed in a number of human tumours, is sufficient to overcome the S-phase checkpoint efficiency thus leading to replicative stress and genomic instability.
Bugler
Béatrix
B
Université de Toulouse, LBCMCP, Toulouse, France.
Schmitt
Estelle
E
Aressy
Bernadette
B
Ducommun
Bernard
B
D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D043171:Chromosomal Instability; D004249:DNA Damage; D006657:Histones / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D016196:S Phase; D013194:Staining and Labeling; D013312:Stress, Physiological; D020687:cdc25 Phosphatases / Q000378:metabolism*
C113571:CDC45 protein, human; D018797:Cell Cycle Proteins; D002843:Chromatin; C468783:H2AX protein, human; D006657:Histones; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases