Shreeram S, Hee WK and Bulavin DV.
The cell division cycle 25A (Cdc25A) phosphatase is a critical regulator
of cell cycle progression under normal conditions and after stress.
Stress-induced degradation of Cdc25A has been proposed as a major way of
delaying cell cycle progression. In vitro studies pointed towards serine 123
as a key site in regulation of Cdc25A stability after exposure to ionizing
radiation (IR). To address the role of this phosphorylation site in vivo,
we generated a knock-in mouse in which serine 123 was substituted for alanine.
The Cdc25 Ser123A knock-in mice appeared normal, and, unexpectedly,
cells derived from them exhibited unperturbed cell cycle and DNA damage
responses. In turn, we found that Cdc25A was present in centrosomes
and that Cdc25A levels were not reduced after IR in knock-in cells.
This resulted in centrosome amplification due to lack of induction of
Cdk2 inhibitory phosphorylation after IR specifically in centrosomes.
Further, Cdc25A knock-in animals appeared sensitive to IR-induced
carcinogenesis. Our findings indicate that Cdc25A Ser123 phosphorylation
is crucial for coupling centrosome duplication to DNA replication cycles
after DNA damage, and therefore is likely to play a role in
the regulation of tumorigenesis.