The Function of Cdc14B in DNA Damage Repair and Tumorigenesis

描述（由申请方提供）：Cdc 14是芽殖酵母中有丝分裂退出所需的Ser/Thr磷酸酶。在哺乳动物中有两种同源物，Cdc 14 A和B。我们已经产生了条件Cdc 14 B基因敲除小鼠。初步研究表明，Cdc 14 B的缺失降低了小鼠的生育能力，但更引人注目的是，突变小鼠以非常高的速度发展白内障，这表明这些动物过早衰老。这种衰老表型与最近报道的Cdc 14 B在DNA损伤修复中的作用一致。Cdc 14 B还通过激活（去磷酸化）Cdh 1（其使有丝分裂激酶Plk 1保持在低水平）而有助于G2/M DNA损伤检查点。Cdc 14 B存在于核仁中，但在DNA损伤时易位到核仁中。调节这种磷酸酶定位的机制尚不清楚，也不知道Cdc 14 B在DNA损伤修复中如何发挥作用。基于我们的初步结果，我们提出，DNA损伤检查点激酶1（Chk 1）调节Cdc 14 B的定位和Cdc 14 B正调控Nek 1，使有效的DNA损伤修复。Cdc 14 B的缺失导致细胞DNA损伤的积累，这会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Cdc 14 B定位如何响应DNA损伤进行调节，2）显示Cdc 14 B如何在DNA损伤修复中发挥作用，3）确定Cdc 14 B是否作为肿瘤抑制因子发挥作用。本文提出的工作将为DNA损伤修复提供新的线索，这是人类健康所必需的过程。

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.