Targeted disruption of NBS1 reveals its roles in mouse development and DNA repair

被引:141
|
作者
Kang, J
Bronson, RT
Xu, Y
机构
[1] Univ Calif San Diego, Mol Biol Sect, Div Biol, La Jolla, CA 92093 USA
[2] Tufts Univ, Sch Med, Dept Pathol, Boston, MA 02111 USA
来源
EMBO JOURNAL | 2002年 / 21卷 / 06期
关键词
cancer; cell cycle; DNA repair; genetic stability; immunodeficiency;
D O I
10.1093/emboj/21.6.1447
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
Nijmegen breakage syndrome (NBS) is an autosomal recessive hereditary disease that shares some common defects with ataxia-telangiectasia. The gene product mutated in NBS, named NBS1, is a component of the Mre11 complex that is involved in DNA strand-break repair. To elucidate the physiological roles of NBS1, we disrupted the N-terminal exons of the NBS1 gene in mice. NBS1(m/m) mice are viable, growth retarded and hypersensitive to ionizing radiation (IR). NBS1(m/m) mice exhibit multiple lymphoid developmental defects, and rapidly develop thymic lymphoma. In addition, female NBS1(m/m) mice are sterile due to oogenesis failure. NBS1(m/m) cells are impaired in cellular responses to IR and defective in cellular proliferation. Most systematic and cellular defects identified in NBS1(m/m) mice recapitulate those in NBS patients, and are essentially identical to those observed in Atm(-/-) mice. In contrast to Atm(-/-) mice, spermatogenesis is normal in NBS1(m/m) mice, indicating that distinct roles of ATM have differential requirement for NBS1 activity. Thus, NBS1 and ATM have overlapping and distinct functions in animal development and DNA repair.
引用
收藏
页码:1447 / 1455
页数:9
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