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.

Public Health Relevance

We will carry out experiments designed to understand how Cdc14B function in DNA damage repair. This function is critical for the health of animals. Mice lacking Cdc14B are prematurely aging. We will also determine if Cdc14B plays a tumor-suppressor role.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA116097-09
Application #
8681379
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Pelroy, Richard
Project Start
2005-06-01
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
9
Fiscal Year
2014
Total Cost
$261,640
Indirect Cost
$94,458
Name
Baylor College of Medicine
Department
Physiology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Hatcher, Rashieda J; Dong, Jie; Liu, Shuang et al. (2014) Pttg1/securin is required for the branching morphogenesis of the mammary gland and suppresses mammary tumorigenesis. Proc Natl Acad Sci U S A 111:1008-13
O'Hara, Laura; York, Jean Philippe; Zhang, Pumin et al. (2014) Targeting of GFP-Cre to the mouse Cyp11a1 locus both drives cre recombinase expression in steroidogenic cells and permits generation of Cyp11a1 knock out mice. PLoS One 9:e84541
Fan, Yihui; Mao, Renfang; Yu, Yang et al. (2014) USP21 negatively regulates antiviral response by acting as a RIG-I deubiquitinase. J Exp Med 211:313-28
Zhang, Wei; Peng, Guang; Lin, Shiaw-Yih et al. (2011) DNA damage response is suppressed by the high cyclin-dependent kinase 1 activity in mitotic mammalian cells. J Biol Chem 286:35899-905
Wei, Zhubo; Peddibhotla, Sirisha; Lin, Han et al. (2011) Early-onset aging and defective DNA damage response in Cdc14b-deficient mice. Mol Cell Biol 31:1470-7
Fang, Xiao; Zhang, Pumin (2011) Aneuploidy and tumorigenesis. Semin Cell Dev Biol 22:595-601
Peddibhotla, Sirisha; Wei, Zhubo; Papineni, Rao et al. (2011) The DNA damage effector Chk1 kinase regulates Cdc14B nucleolar shuttling during cell cycle progression. Cell Cycle 10:671-9
Chao, Wei-Ting; Ashcroft, Felicity; Daquinag, Alexes C et al. (2010) Type I phosphatidylinositol phosphate kinase beta regulates focal adhesion disassembly by promoting beta1 integrin endocytosis. Mol Cell Biol 30:4463-79
Liang, Yulong; Gao, Hong; Lin, Shiaw-Yih et al. (2010) BRIT1/MCPH1 is essential for mitotic and meiotic recombination DNA repair and maintaining genomic stability in mice. PLoS Genet 6:e1000826
Gao, Xue; Shin, Yong-Hyun; Li, Min et al. (2010) The fat mass and obesity associated gene FTO functions in the brain to regulate postnatal growth in mice. PLoS One 5:e14005

Showing the most recent 10 out of 21 publications