SV40 T antigen interacts with Nbs1 to disrupt DNA replication control
- Xiaohua Wu1,2,4,
- Dror Avni1,
- Takuya Chiba2,
- Feng Yan2,
- Qiping Zhao2,
- Yafang Lin1,
- Henry Heng3, and
- David Livingston1,5
- 1Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA; 2The Scripps Research Institute, Department of Molecular and Experimental Medicine, La Jolla, California 92037, USA; 3Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan 48202, USA
Abstract
Nijmegen breakage syndrome (NBS) is characterized by radiation hypersensitivity, chromosomal instability, and predisposition to cancer. Nbs1, the NBS protein, forms a tight complex with Mre11 and Rad50, and these interactions contribute to proper double-strand break repair. The simian virus 40 (SV40) oncoprotein, large T antigen (T), also interacts with Nbs1, and T-containing cells experience chromosomal hyperreplication in a manner dependent on T/Nbs1 complex formation. A substantial fraction of NBS-deficient fibroblasts reinitiate DNA replication in discrete regions, and wild-type Nbs1 corrects this defect. Similarly, synthesis of an N-terminal Nbs1 fragment induced DNA rereplication and tetraploidy, in NBS-deficient but not NBS-proficient cells. Moreover, SV40 origin-containing DNA hyperreplicated in T-containing NBS-deficient cells by comparison with T-containing, Nbs1-reconstituted derivatives. Thus, Nbs1 suppresses rereplication of cellular DNA and SV40 origin-containing replicons, and T targets Nbs1, thereby enhancing the yield of new SV40 genomes during viral DNA replication.
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Footnotes
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Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1182804.
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Corresponding author.
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↵4 E-MAIL xiaohwu{at}scripps.edu; FAX (858) 784-7978
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↵5 E-MAIL david_livingston{at}dfcl.harvard.edu; FAX (617) 632-4381.
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- Accepted April 12, 2004.
- Received December 30, 2003.
- Cold Spring Harbor Laboratory Press
