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Originally published In Press as doi:10.1074/jbc.M205189200 on June 25, 2002

J. Biol. Chem., Vol. 277, Issue 37, 34549-34555, September 13, 2002
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Targeted Disruption of Np95 Gene Renders Murine Embryonic Stem Cells Hypersensitive to DNA Damaging Agents and DNA Replication Blocks*

Masahiro MutoDagger §, Yasuyoshi KanariDagger §, Eiko KuboDagger , Tamami TakabeDagger , Takayuki Kurihara||, Akira FujimoriDagger , and Kouichi TatsumiDagger **

From the Dagger  Research Center for Radiation Safety, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba 263-8555, Japan and the || Division of Basic Sciences, Medical Research Institute, Kanazawa Medical University, Ishikawa 920-0293, Japan

NP95, which contains a ubiquitin-like domain, a cyclin A/E-Cdk2 phosphorylation site, a retinoblastoma (Rb) binding motif, and a ring finger domain, has been shown to be colocalized as foci with proliferating cell nuclear antigen in early and mid-S phase nuclei. We established Np95 nulligous embryonic stem cells by replacing the exons 2-7 of the Np95 gene with a neo cassette and by selecting out a spontaneously occurring homologous chromosome crossing over with a higher concentration of neomycin. Np95-null cells were more sensitive to x-rays, UV light, N-methyl-N''-nitro-N-nitrosoguanidine (MNNG), and hydroxyurea than embryonic stem wild type (Np95+/+) or heterozygously inactivated (Np95+/-) cells. Expression of transfected Np95 cDNA in Np95-null cells restored the resistance to x-rays, UV, MNNG, or hydroxyurea concurrently to a level similar to that of Np95+/- cells, although slightly below that of wild type (Np95+/+) cells. These findings suggest that NP95 plays a role in the repair of DNA damage incurred by these agents. The frequency of spontaneous sister chromatid exchange was significantly higher for Np95-null cells than for Np95+/+ cells or Np95+/- cells (p < 0.001). We conclude that NP95 functions as a common component in the multiple response pathways against DNA damage and replication arrest and thereby contributes to genomic stability.

* This work was supported by a Grant for the Project Research "Genetic Control of Biodefense Mechanisms against Radiation" from the Science and Technology Agency, Japan, and in part by a Grant-in-Aid for Scientific Research (Grant 09680540) from the Ministry of Education, Science, Sports and Culture of Japan.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AB066245

§ These authors contributed equally to this study.

Present address: Dept. of Immunology, Kinki University School of Medicine 377-2 Ohno-Higashi, Sayama, Osaka 589-8511, Japan.

** To whom correspondence should be addressed. Tel.: 81-43-206-3091; Fax: 81-43-251-4593; E-mail: tatsumi@nirs.go.jp.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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