The Function of Cdc14B in DNA Damage Repair and Tumorigenesis

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DESCRIPTION (provided by applicant): Cdc14 is a Ser/Thr phosphatase required for mitotic exit in budding yeasts. There are two homologues in mammals, Cdc14A and B. We have generated conditional Cdc14B knockout mice. Preliminary studies indicated that loss of Cdc14B reduces fertility in mice, but more strikingly, the mutant mice develop cataracts at very high rates, suggesting that these animals are aging prematurely. This aging phenotype is consistent with a role of Cdc14B in DNA damage repair as reported recently. Cdc14B also contributes to the G2/M DNA damage checkpoint by activating (dephosphorylating) Cdh1 which keeps the mitotic kinase Plk1 at low levels. Cdc14B resides in nucleolus but translocates to the nucleolus in response to DNA damage. The mechanism that regulates the localization of this phosphatase is not known, nor is it known how Cdc14B functions in DNA damage repair. Based on our preliminary results, we propose that DNA damage checkpoint kinase 1 (Chk1) regulates Cdc14B's localization and Cdc14B positively regulates Nek1 to allow efficient DNA damage repair. Loss of Cdc14B results in the accumulation of cellular DNA damage which causes premature aging and mutations that lead to tumorigenesis. To test this hypothesis, we proposed the following specific aims: 1) To determine how Cdc14B localization is regulated in response to DNA damage, 2) To show how Cdc14B functions in DNA damage repair, and 3) To determine if Cdc14B functions as a tumor suppressor. The work proposed here will shed new light on DNA damage repair, a process essential for human health.