Early-onset aging and defective DNA damage response in Cdc14b-deficient mice.
The Cdc14 dual-specificity phosphatase plays a key role in the mitotic exit of budding yeast cells. Mammals have two homologues, Cdc14a and Cdc14b. Unlike the yeast counterpart, neither Cdc14a nor Cdc14b seems to be essential for mitotic exit. To determine the physiological function of Cdc14b, we generated mice deficient in the phosphatase. The mutant mice were viable and did not display overt abnormalities. However, these mice developed signs of aging at much younger ages than the wild-type mice. At the cellular level, the Cdc14b-deficient mouse embryonic fibroblasts (MEFs) grew more slowly than the controls at later passages as a result of increased rates of senescence. Consistent with these premature-aging phenotypes, Cdc14b-deficient cells accumulated more endogenous DNA damage than the wild-type cells, and more Cdc14b-deficient MEFs entered senescence than control MEFs in response to exogenous DNA damage. However, no deficiencies in DNA damage checkpoint response were detected in Cdc14b mutant cells, suggesting that the function of Cdc14b is required for efficient DNA damage repair.
Department of Molecular Physiology and Biophysics, BCM335, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Zhubo
Z
Wei
Sirisha
S
Peddibhotla
Han
H
Lin
Xiao
X
Fang
Min
M
Li
Jeffrey M
JM
Rosen
Pumin
P
Zhang
D019588:Aging, Premature / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D016922:Cellular Senescence; D004249:DNA Damage; D004260:DNA Repair; D054637:Dual-Specificity Phosphatases / Q000172:deficiency* / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D005298:Fertility; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D016195:G2 Phase; D008568:Memory; D051379:Mice; D008938:Mitosis
C541950:CDC14B protein, mouse; D054637:Dual-Specificity Phosphatases
Nat Cell Biol. 2009 May;11(5):644-51
19396163
Nat Cell Biol. 2010 Sep;12(9):886-93
20711181
Biol Reprod. 2009 Apr;80(4):795-803
19129509
Nature. 2009 Oct 22;461(7267):1071-8
19847258
J Cell Biol. 2010 May 17;189(4):631-9
20479464
N Engl J Med. 2009 Oct 8;361(15):1475-85
19812404
Annu Rev Genet. 2004;38:203-32
15568976
Cell Cycle. 2009 Apr 1;8(7):1090-8
19270517
EMBO J. 2008 Feb 20;27(4):679-91
18239684
Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9363-7
7568133
Nat Cell Biol. 2008 Sep;10(9):1083-9
19160489
Mol Cell. 2009 Oct 9;36(1):2-14
19818705
Nature. 1993 Apr 22;362(6422):709-15
8469282
J Cell Biol. 2008 May 5;181(3):475-83
18458157
Cell Cycle. 2008 May 1;7(9):1184-90
18418058
Mol Biol Cell. 2002 Jul;13(7):2289-300
12134069
EMBO J. 2010 May 19;29(10):1726-37
20424596
Mol Cell Biol. 2005 Jun;25(11):4541-51
15899858
J Cell Biol. 1963 May;17:299-313
13985244
Nat Cell Biol. 2008 Jul;10(7):802-11
18552834
Genesis. 2000 Feb;26(2):113-5
10686601
Nat Cell Biol. 2002 Apr;4(4):317-22
11901424
J Biol Chem. 1997 Nov 21;272(47):29403-6
9367992
Cell. 2008 Jul 25;134(2):256-67
18662541
Front Biosci. 2003 Sep 01;8:d1275-87
12957817