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 #
2R01CA116097-06
Application #
8108110
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Pelroy, Richard
Project Start
2005-06-01
Project End
2016-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
6
Fiscal Year
2011
Total Cost
$269,732
Indirect Cost
Name
Baylor College of Medicine
Department
Physiology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Fang, Xiao; Lu, Guojun; Ha, Kyungsoo et al. (2018) Acetylation of TIP60 at K104 is essential for metabolic stress-induced apoptosis in cells of hepatocellular cancer. Exp Cell Res 362:279-286
Ha, Kyungsoo; Ma, Chengxian; Lin, Han et al. (2017) The anaphase promoting complex impacts repair choice by protecting ubiquitin signalling at DNA damage sites. Nat Commun 8:15751
Chen, Ruoyu; Zhang, Qiao; Duan, Xiaoya et al. (2017) The 5-Hydroxymethylcytosine (5hmC) Reader UHRF2 Is Required for Normal Levels of 5hmC in Mouse Adult Brain and Spatial Learning and Memory. J Biol Chem 292:4533-4543
Li, Zejuan; Weng, Hengyou; Su, Rui et al. (2017) FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N6-Methyladenosine RNA Demethylase. Cancer Cell 31:127-141
Cheng, Ranran; Liang, Xin; Zhao, Quancheng et al. (2017) APCCdh1 controls cell cycle entry during liver regeneration. Exp Cell Res 354:78-84
Ding, Chen; Li, Yanyan; Guo, Feifei et al. (2016) A Cell-type-resolved Liver Proteome. Mol Cell Proteomics 15:3190-3202
Zhang, Haoxing; Liu, Hailong; Chen, Yali et al. (2016) A cell cycle-dependent BRCA1-UHRF1 cascade regulates DNA double-strand break repair pathway choice. Nat Commun 7:10201
York, J Philippe; Ren, Yi Athena; Zeng, Jie et al. (2016) Growth Arrest Specific 2 (GAS2) is a Critical Mediator of Germ Cell Cyst Breakdown and Folliculogenesis in Mice. Sci Rep 6:34956
Tang, Lichun; Gong, Mengmeng; Zhang, Pumin (2016) In vitro CRISPR-Cas9-mediated efficient Ad5 vector modification. Biochem Biophys Res Commun 474:395-399
Stratigopoulos, George; Burnett, Lisa Cole; Rausch, Richard et al. (2016) Hypomorphism of Fto and Rpgrip1l causes obesity in mice. J Clin Invest 126:1897-910

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