The Function of Cdc14B in DNA Damage Repair and Tumorigenesis

描述（由申请人提供）：Cdc14是出芽酵母有丝分裂退出所需的丝氨酸/苏氨酸磷酸酶。在哺乳动物中有两个同源物，Cdc14A和b。我们已经产生了条件Cdc14B敲除小鼠。初步研究表明，缺失Cdc14B会降低小鼠的生育能力，但更令人惊讶的是，突变小鼠患白内障的几率非常高，这表明这些动物正在过早衰老。这种衰老表型与最近报道的Cdc14B在DNA损伤修复中的作用一致。Cdc14B还通过激活（去磷酸化）Cdh1来促进G2/M DNA损伤检查点，使有丝分裂激酶Plk1保持在低水平。Cdc14B存在于核仁中，但在DNA损伤时易位到核仁中。调控这种磷酸酶定位的机制尚不清楚，也不知道Cdc14B在DNA损伤修复中的作用。基于我们的初步结果，我们提出DNA损伤检查点激酶1 （Chk1）调节Cdc14B的定位，Cdc14B正调控Nek1以实现有效的DNA损伤修复。Cdc14B的缺失导致细胞DNA损伤的积累，从而导致过早衰老和导致肿瘤发生的突变。为了验证这一假设，我们提出了以下具体目标：1)确定Cdc14B定位在DNA损伤响应中是如何调节的；2)显示Cdc14B在DNA损伤修复中的功能；3)确定Cdc14B是否具有肿瘤抑制作用。这里提出的工作将为DNA损伤修复这一对人类健康至关重要的过程提供新的线索。

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.