N. Rhind et al., CDC2 TYROSINE PHOSPHORYLATION IS REQUIRED FOR THE DNA-DAMAGE CHECKPOINT IN FISSION YEAST, Genes & development, 11(4), 1997, pp. 504-511
A common cellular response to DNA damage is cell cycle arrest. This ch
eckpoint control has been the subject of intensive genetic investigati
on, but the biochemical mechanism that prevents mitosis following DNA
damage is unknown. In Schizosaccharomyces pombe, as well as vertebrate
s, the timing of mitosis under normal circumstances is determined by t
he balance of kinases and phosphatases that regulate inhibitory phosph
orylation of Cdc2. In S. pombe, the phosphorylation occurs on tyrosine
-15. This method of mitotic control is also used in S. pombe to couple
mitosis with completion of DNA replication, but the role of Cdc2 tyro
sine phosphorylation in the Chk1 kinase-mediated DNA damage checkpoint
has remained uncertain. We show that, in contrast to recent speculati
on, the G(2) DNA damage checkpoint arrest in S. pombe depends on the i
nhibitory tyrosine phosphorylation of Cdc2 carried out by the Wee1 and
Mik1 kinases. furthermore, the rate of Cdc2 tyrosine dephosphorylatio
n is reduced by irradiation. This result implicates regulation of Cdc2
tyrosine dephosphorylation, mainly carried out by the Cdc25 tyrosine
phosphatase, as an important part of the mechanism by which the DNA da
mage checkpoint induces Cdc2 inhibition and G(2) arrest.