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Molecular and Cellular Biology, March 1999, p. 2366-2372, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Postnatal Growth Failure, Short Life Span, and Early Onset of Cellular Senescence and Subsequent Immortalization in Mice Lacking the Xeroderma Pigmentosum Group G Gene

Yoshi-Nobu Harada,1 Naoko Shiomi,1 Manabu Koike,1 Masahito Ikawa,2 Masaru Okabe,2 Seiichi Hirota,3 Yukihiko Kitamura,3 Masanobu Kitagawa,4 Tsukasa Matsunaga,5 Osamu Nikaido,5 and Tadahiro Shiomi1,*

The Genome Research Group, National Institute of Radiological Sciences, Inage-ku, Chiba 263,1 Research Institute for Microbial Diseases, Osaka University,2 and Department of Pathology, Osaka University Medical School,3 Osaka 565, Department of Pathology and Immunology, Faculty of Medicine, Tokyo Medical and Dental University, Tokyo 113,4 and Division of Radiation Biology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa 920,5 Japan

Received 5 October 1998/Returned for modification 2 December 1998/Accepted 11 December 1998

The xeroderma pigmentosum group G (XP-G) gene (XPG) encodes a structure-specific DNA endonuclease that functions in nucleotide excision repair (NER). XP-G patients show various symptoms, ranging from mild cutaneous abnormalities to severe dermatological impairments. In some cases, patients exhibit growth failure and life-shortening and neurological dysfunctions, which are characteristics of Cockayne syndrome (CS). The known XPG protein function as the 3' nuclease in NER, however, cannot explain the development of CS in certain XP-G patients. To gain an insight into the functions of the XPG protein, we have generated and examined mice lacking xpg (the mouse counterpart of the human XPG gene) alleles. The xpg-deficient mice exhibited postnatal growth failure and underwent premature death. Since XPA-deficient mice, which are totally defective in NER, do not show such symptoms, our data indicate that XPG performs an additional function(s) besides its role in NER. Our in vitro studies showed that primary embryonic fibroblasts isolated from the xpg-deficient mice underwent premature senescence and exhibited the early onset of immortalization and accumulation of p53.

* Corresponding author. Mailing address: The Genome Research Group, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263, Japan. Phone: 81-43-206-3136. Fax: 81-43-251-9818. E-mail: shiomita{at}nirs.gp.jp.

Molecular and Cellular Biology, March 1999, p. 2366-2372, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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