Once a cell divides, the daughter cells must return to a ground state (characterized by low cyclin-dependent kinase [CDK] activities) to prepare for another division cycle or, alternatively, to withdraw from the cell cycle. Failure to return to the ground state is associated with unscheduled cell cycle entry and developmental defects in animals. Establishment of this ground state requires not only inhibition of the mitotic kinase CDK1/cyclin B1, but also the dephosphorylation of a large number of CDK1-phosphorylated proteins. The dephosphorylation is carried out primarily by Cdc14 in budding yeasts (3
). Despite the presence of two Cdc14 homologues in mammals, Cdc14b was considered much closer to yeast Cdc14 based on their common subcellular localization in the nucleolus. However, a definitive function of Cdc14b in mitotic exit has never been established. In fact, the phosphatase(s) required for mitotic exit in higher eukaryotes seems unrelated to Cdc14. For example, in Xenopus
, protein phosphatase 1 (PP1) was shown to catalyze dephosphorylation during mitotic exit (24
), and recently, PP2A-B55α was identified as the mitotic exit phosphatase in human cells (19
). The lack of mitotic phenotypes in cells with Cdc14a (15
) or Cdc14b (reference 4
and this study) deleted unequivocally demonstrates that the mammalian Cdc14 phosphatases do not regulate mitosis. They must have gained other functions during evolution.
Aging (and cellular senescence) is triggered by cellular stresses, including DNA damage (1
). The genetic material in a cell is constantly assaulted by endogenous metabolic by-products, such as reactive oxygen species, and by exogenous physical and chemical genotoxic agents. It is estimated that there are about 105
lesions per cell per day in humans (13
). In response to such high levels of DNA damage, sophisticated mechanisms have evolved to coordinate cell cycle progression and repair. When the damage is too extensive to repair, the damaged cells are eliminated by apoptosis, as they may impose adverse effects on the well-being of a multicellular organism or enter senescence, a state of permanent arrest. The aging phenotypes of Cdc14b-deficient mice suggest a role of the phosphatase in the DNA damage response. Bassermann et al. (2
) reported that Cdc14b contributed to the G2
/M DNA damage checkpoint by activating APCCdh1
. However, we did not observe any checkpoint defects in the Cdc14b-deficeint MEFs. A similar result was reported recently using HCT116 and DT-40 cells with CDC14B
). Instead, our results, and those obtained from human and chicken cells indicate that Cdc14b is required for efficient DNA damage repair.
It is unclear how Cdc14b functions in DNA damage repair. It is likely that Cdc14b dephosphorylates substrates involved in DNA damage repair. Given that Cdc14a is also required for efficient DNA damage repair (15
), it is plausible that these two homologous phosphatases target the same set of substrates, although neither is sufficient. Identification of the relevant substrates in future studies will be the key to understanding how Cdc14 phosphatases regulate the DNA repair process.