This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dendouga, N.
Right arrow Articles by McGowan, C. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dendouga, N.
Right arrow Articles by McGowan, C. H.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, September 2005, p. 7569-7579, Vol. 25, No. 17
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.17.7569-7579.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Disruption of Murine Mus81 Increases Genomic Instability and DNA Damage Sensitivity but Does Not Promote Tumorigenesis

Najoua Dendouga,1,{dagger} Hui Gao,2,{dagger} Dieder Moechars,3 Michel Janicot,1 Jorge Vialard,1 and Clare H. McGowan2,4*

Department of Molecular Biology,2 Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037,4 Oncology Discovery Research and Early Development Europe,1 Functional Genomics Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium3

Received 16 May 2005/ Returned for modification 3 June 2005/ Accepted 15 June 2005

The Mus81-Eme1 endonuclease is implicated in the efficient rescue of broken replication forks in Saccharomyces cerevisiae and Schizosaccharomyces pombe. We have used gene targeting to study the function of the Mus81-Eme1 endonuclease in mammalian cells. Mus81-deficient mice develop normally and are fertile. Surprisingly, embryonic fibroblasts from Mus81–/– animals fail to proliferate in vitro. This proliferation defect can be rescued by expression of the papillomavirus E6 protein that promotes degradation of p53. When grown in culture, Mus81–/– cells have elevated levels of DNA damage, acquire chromosomal aberrations, and are hypersensitive to agents that generate DNA cross-links. In contrast to the situation in yeast, murine Mus81 is not required for replication restart following camptothecin treatment. Mus81–/– mice and cells are hypersensitive to DNA cross-linking agents. Cross-link-induced double-strand break formation is normal in Mus81–/– cells, but the resolution of repair intermediates is not. The persistence of Rad51 foci in Mus81–/– cells suggests that Mus81 acts at a late step in the repair of cross-link-induced lesions. Despite these defects, Mus81–/– mice do not show increased predisposition to lymphoma or any other malignancy in the first year of life.

* Corresponding author. Mailing address: Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-2280. Fax: (858) 784-2265. E-mail: chmcg{at}scripps.edu.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, September 2005, p. 7569-7579, Vol. 25, No. 17
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.17.7569-7579.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Horiguchi, M., Inoue, T., Ohbayashi, T., Hirai, M., Noda, K., Marmorstein, L. Y., Yabe, D., Takagi, K., Akama, T. O., Kita, T., Kimura, T., Nakamura, T. (2009). Fibulin-4 conducts proper elastogenesis via interaction with cross-linking enzyme lysyl oxidase. Proc. Natl. Acad. Sci. USA 106: 19029-19034 [Abstract] [Full Text]  
  • Franchitto, A., Pirzio, L. M., Prosperi, E., Sapora, O., Bignami, M., Pichierri, P. (2008). Replication fork stalling in WRN-deficient cells is overcome by prompt activation of a MUS81-dependent pathway. JCB 183: 241-252 [Abstract] [Full Text]  
  • Ehmsen, K. T., Heyer, W.-D. (2008). Saccharomyces cerevisiae Mus81-Mms4 is a catalytic, DNA structure-selective endonuclease. Nucleic Acids Res 36: 2182-2195 [Abstract] [Full Text]  
  • Svetlanov, A., Baudat, F., Cohen, P. E., de Massy, B. (2008). Distinct Functions of MLH3 at Recombination Hot Spots in the Mouse. Genetics 178: 1937-1945 [Abstract] [Full Text]  
  • Taylor, E. R., McGowan, C. H. (2008). Cleavage mechanism of human Mus81-Eme1 acting on Holliday-junction structures. Proc. Natl. Acad. Sci. USA 105: 3757-3762 [Abstract] [Full Text]  
  • Vigneron, A., Gamelin, E., Coqueret, O. (2008). The EGFR-STAT3 Oncogenic Pathway Up-regulates the Eme1 Endonuclease to Reduce DNA Damage after Topoisomerase I Inhibition. Cancer Res. 68: 815-825 [Abstract] [Full Text]  
  • Fisher, L. A., Bessho, M., Bessho, T. (2008). Processing of a Psoralen DNA Interstrand Cross-link by XPF-ERCC1 Complex in Vitro. J. Biol. Chem. 283: 1275-1281 [Abstract] [Full Text]  
  • Nomura, Y., Adachi, N., Koyama, H. (2007). Human Mus81 and FANCB independently contribute to repair of DNA damage during replication. GENES CELLS 12: 1111-1122 [Abstract] [Full Text]  
  • Pamidi, A., Cardoso, R., Hakem, A., Matysiak-Zablocki, E., Poonepalli, A., Tamblyn, L., Perez-Ordonez, B., Hande, M. P., Sanchez, O., Hakem, R. (2007). Functional Interplay of p53 and Mus81 in DNA Damage Responses and Cancer. Cancer Res. 67: 8527-8535 [Abstract] [Full Text]  
  • Trowbridge, K., McKim, K., Brill, S. J., Sekelsky, J. (2007). Synthetic Lethality of Drosophila in the Absence of the MUS81 Endonuclease and the DmBlm Helicase Is Associated With Elevated Apoptosis. Genetics 176: 1993-2001 [Abstract] [Full Text]  
  • Mimida, N., Kitamoto, H., Osakabe, K., Nakashima, M., Ito, Y., Heyer, W.-D., Toki, S., Ichikawa, H. (2007). Two Alternatively Spliced Transcripts Generated from OsMUS81, a Rice Homolog of Yeast MUS81, Are Up-Regulated by DNA-Damaging Treatments. Plant Cell Physiol 48: 648-654 [Abstract] [Full Text]  
  • Hanada, K., Vermeij, M., Garinis, G. A., de Waard, M. C., Kunen, M. G.S., Myers, L., Maas, A., Duncker, D. J., Meijers, C., Dietz, H. C., Kanaar, R., Essers, J. (2007). Perturbations of Vascular Homeostasis and Aortic Valve Abnormalities in Fibulin-4 Deficient Mice. Circ. Res. 100: 738-746 [Abstract] [Full Text]  
  • Kuznetsov, S., Pellegrini, M., Shuda, K., Fernandez-Capetillo, O., Liu, Y., Martin, B. K., Burkett, S., Southon, E., Pati, D., Tessarollo, L., West, S. C., Donovan, P. J., Nussenzweig, A., Sharan, S. K. (2007). RAD51C deficiency in mice results in early prophase I arrest in males and sister chromatid separation at metaphase II in females. JCB 176: 581-592 [Abstract] [Full Text]  
  • Hartung, F., Suer, S., Bergmann, T., Puchta, H. (2006). The role of AtMUS81 in DNA repair and its genetic interaction with the helicase AtRecQ4A. Nucleic Acids Res 34: 4438-4448 [Abstract] [Full Text]  
  • Hiyama, T., Katsura, M., Yoshihara, T., Ishida, M., Kinomura, A., Tonda, T., Asahara, T., Miyagawa, K. (2006). Haploinsufficiency of the Mus81-Eme1 endonuclease activates the intra-S-phase and G2/M checkpoints and promotes rereplication in human cells. Nucleic Acids Res 34: 880-892 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»