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Molecular and Cellular Biology, July 2000, p. 4553-4561, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Disruption of Mouse SNM1 Causes Increased Sensitivity to the DNA Interstrand Cross-Linking Agent Mitomycin C

Mies L. G. Dronkert,1 Jan de Wit,1 Miranda Boeve,2 M. Luisa Vasconcelos,1,dagger Harry van Steeg,2 T. L. Raoul Tan,1 Jan H. J. Hoeijmakers,1 and Roland Kanaar1,3,*

Department of Cell Biology and Genetics, Centre for Biomedical Genetics, Erasmus University Rotterdam,1 and Department of Radiation Oncology, Daniël den Hoed Cancer Center,3 3000 DR Rotterdam, and Laboratory of Health Effects Research, National Institute of Public Health and the Environment, 3720 BA Bilthoven,2 The Netherlands

Received 20 December 1999/Returned for modification 16 February 2000/Accepted 5 April 2000

DNA interstrand cross-links (ICLs) represent lethal DNA damage, because they block transcription, replication, and segregation of DNA. Because of their genotoxicity, agents inducing ICLs are often used in antitumor therapy. The repair of ICLs is complex and involves proteins belonging to nucleotide excision, recombination, and translesion DNA repair pathways in Escherichia coli, Saccharomyces cerevisiae, and mammals. We cloned and analyzed mammalian homologs of the S. cerevisiae gene SNM1 (PSO2), which is specifically involved in ICL repair. Human Snm1, a nuclear protein, was ubiquitously expressed at a very low level. We generated mouse SNM1-/- embryonic stem cells and showed that these cells were sensitive to mitomycin C. In contrast to S. cerevisiae snm1 mutants, they were not significantly sensitive to other ICL agents, probably due to redundancy in mammalian ICL repair and the existence of other SNM1 homologs. The sensitivity to mitomycin C was complemented by transfection of the human SNM1 cDNA and by targeting of a genomic cDNA-murine SNM1 fusion construct to the disrupted locus. We also generated mice deficient for murine SNM1. They were viable and fertile and showed no major abnormalities. However, they were sensitive to mitomycin C. The ICL sensitivity of the mammalian SNM1 mutant suggests that SNM1 function and, by implication, ICL repair are at least partially conserved between S. cerevisiae and mammals.

* Corresponding author. Mailing address: Department of Cell Biology and Genetics, Erasmus University Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. Phone: 31-10-4087168. Fax: 31-10-4089468. E-mail: kanaar{at}gen.fgg.eur.nl.

dagger Present address: Department of Biological Chemistry, Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095-1662.

Molecular and Cellular Biology, July 2000, p. 4553-4561, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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