Synthetic lethality between mutation in Atm and DNA-PKcs during murine embryogenesis

被引:115
作者
Gurley, KE [1 ]
Kemp, CJ [1 ]
机构
[1] Fred Hutchinson Canc Res Ctr C1 015, Seattle, WA USA
基金
美国国家卫生研究院;
关键词
D O I
10.1016/S0960-9822(01)00048-3
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The gene product mutated in ataxia telangiectasia, ATM, is a ubiquitously expressed 370 kDa protein kinase that is a key mediator of the cellular response to DNA damage [1], ATM-deficient cells are radiosensitive and show impaired cell cycle arrest and increased chromosome breaks in response to ionizing radiation. ATM is a member of the phosphatidylinositol-3-kinase (Pl3K)-related protein kinase superfamily, which includes the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) and ATR [2], DNA-PK is a 470 kDa protein kinase that is required for proper end-to-end rejoining of DNA double-strand breaks [3], Prkdc(scid/scid) mice have a homozygous mutation in the gene encoding DNA-PK, and, like Atm(-/-) mice, are viable and radiosensitive [4-8], To determine if Atm and DNA-PK, show genetic interaction, we attempted to generate mice deficient in both gene products. However, no scid/scid Atm(-/-) pups were recovered from scid/scid Atm(-/-) intercrosses. Developmental arrest of scid/scid Atm(-/-) embryos occurred around E7.5, a developmental stage when embryonic cells are hypersensitive to DNA damage [9], This reveals synthetic lethality between mutations in Atm and DNA-PK and suggests that Atm and DNA-PK have complementary functions that are essential for development.
引用
收藏
页码:191 / 194
页数:4
相关论文
共 29 条
[11]   p53 induction, cell cycle checkpoints, and apoptosis in DNAPK-deficient scid mice [J].
Gurley, KE ;
Kemp, CJ .
CARCINOGENESIS, 1996, 17 (12) :2537-2542
[12]  
Gurley KE, 1998, CANCER RES, V58, P3111
[13]   Requirement for Atm in ionizing radiation-induced cell death in the developing central nervous system [J].
Herzog, KH ;
Chong, MJ ;
Kapsetaki, M ;
Morgan, JI ;
McKinnon, PJ .
SCIENCE, 1998, 280 (5366) :1089-1091
[14]  
Heyer BS, 2000, GENE DEV, V14, P2072
[15]   The p53 response to DNA damage in vivo is independent of DNA-dependent protein kinase [J].
Jhappan, C ;
Yusufzai, TM ;
Anderson, S ;
Anver, MR ;
Merlino, G .
MOLECULAR AND CELLULAR BIOLOGY, 2000, 20 (11) :4075-4083
[16]   DNA-dependent protein kinase is not required for the p53-dependent response to DNA damage [J].
Jimenez, GS ;
Bryntesson, F ;
Torres-Arzayus, MI ;
Priestley, A ;
Beeche, M ;
Saito, S ;
Sakaguchi, K ;
Appella, E ;
Jeggo, PA ;
Taccioli, GE ;
Wahl, GM ;
Hubank, M .
NATURE, 1999, 400 (6739) :81-83
[17]   Tying loose ends: Roles of Ku and DNA-dependent protein kinase in the repair of double-strand breaks [J].
Lieber, MR ;
Grawunder, U ;
Wu, XT ;
Yaneva, M .
CURRENT OPINION IN GENETICS & DEVELOPMENT, 1997, 7 (01) :99-104
[18]  
Lim DS, 1996, MOL CELL BIOL, V16, P7133
[19]   A murine AP-endonuclease gene-targeted deficiency with post-implantation embryonic progression and ionizing radiation sensitivity [J].
Ludwig, DL ;
MacInnes, MA ;
Takiguchi, Y ;
Purtymun, PE ;
Henrie, M ;
Flannery, M ;
Meneses, J ;
Pedersen, RA ;
Chen, DJ .
MUTATION RESEARCH-DNA REPAIR, 1998, 409 (01) :17-29
[20]   Disruption of mRad50 causes embryonic stem cell lethality, abnormal embryonic development, and sensitivity to ionizing radiation [J].
Luo, GB ;
Yao, MS ;
Bender, CF ;
Mills, M ;
Bladl, AR ;
Bradley, A ;
Petrini, JHJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (13) :7376-7381