[en] Mus81-Eme1 endonuclease has been implicated in the rescue of stalled replication forks and the resolution of meiotic recombination intermediates in yeast. We used gene targeting to study the physiological requirements of Mus81 in mammals. Mus81-/- mice are viable and fertile, which indicates that mammalian Mus81 is not essential for recombination processes associated with meiosis. Mus81-deficient mice and cells were hypersensitive to the DNA cross-linking agent mitomycin C but not to gamma-irradiation. Remarkably, both homozygous Mus81-/- and heterozygous Mus81+/- mice exhibited a similar susceptibility to spontaneous chromosomal damage and a profound and equivalent predisposition to lymphomas and other cancers. These studies demonstrate a critical role for the proper biallelic expression of the mammalian Mus81 in the maintenance of genomic integrity and tumor suppression.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
McPherson, John Peter; Ontario Cancer Institute, 620 University Avenue, Suite 706, Toronto, Ontario, Canada M5G 2C1
Lemmers, Bénédicte; Ontario Cancer Institute, Toronto, Ont. M5G 2C1, Canada ; Department of Medical Biophysics, University of Toronto, Toronto, Ont. M5G 2M9, Canada
CHAHWAN, Richard ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Health, Medicine and Life Sciences (DHML) ; Ontario Cancer Institute, Toronto, Ont. M5G 2C1, Canada ; Department of Medical Biophysics, University of Toronto, Toronto, Ont. M5G 2M9, Canada
Pamidi, Ashwin; Ontario Cancer Institute, Toronto, Ont. M5G 2C1, Canada ; Department of Medical Biophysics, University of Toronto, Toronto, Ont. M5G 2M9, Canada
Migon, Eva; Ontario Cancer Institute, Toronto, Ont. M5G 2C1, Canada ; Department of Medical Biophysics, University of Toronto, Toronto, Ont. M5G 2M9, Canada
Matysiak-Zablocki, Elzbieta; Ontario Cancer Institute, Toronto, Ont. M5G 2C1, Canada ; Department of Medical Biophysics, University of Toronto, Toronto, Ont. M5G 2M9, Canada
Moynahan, Mary Ellen; Department of Medicine, Mem. Sloan-Kettering Cancer Center, New York, NY 10021, United States
Essers, Jeroen; Dept. of Cell Biology and Genetics, Erasmus MC, University Medical Center, 3000 DR Rotterdam, Netherlands
Hanada, Katsuhiro; Dept. of Cell Biology and Genetics, Erasmus MC, University Medical Center, 3000 DR Rotterdam, Netherlands
Poonepalli, Anuradha; Dept. of Physiol./Oncol. Res. Inst., Faculty of Medicine, National University of Singapore, Singapore 117597, Singapore
Sanchez-Sweatman, Otto; Department of Medical Biophysics, University of Toronto, Toronto, Ont. M5G 2M9, Canada
Khokha, Rama; Department of Medical Biophysics, University of Toronto, Toronto, Ont. M5G 2M9, Canada
Kanaar, Roland; Dept. of Cell Biology and Genetics, Erasmus MC, University Medical Center, 3000 DR Rotterdam, Netherlands
Jasin, Maria; Department of Medicine, Mem. Sloan-Kettering Cancer Center, New York, NY 10021, United States
Hande, M Prakash; Dept. of Physiol./Oncol. Res. Inst., Faculty of Medicine, National University of Singapore, Singapore 117597, Singapore
Hakem, Razqallah; Ontario Cancer Institute, Toronto, Ont. M5G 2C1, Canada ; Department of Medical Biophysics, University of Toronto, Toronto, Ont. M5G 2M9, Canada
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We thank S. West, A. Ciccia, J. Abraham, and A. Hakem for helpful discussions and for reviewing the manuscript; A. Shehabeldin, J. Ho, D. Bouchard, A. Wakeham, and S. Plyte for technical assistance; and R. Laister, S. Duan, and C. Arrowsmith for sharing reagents. We also thank S. West and A. Ciccia for the antiserum against N-terminal Mus81. J.P.M. was supported by a Canadian Institute of Health Research Fellowship. M.P.H. is supported by start-up grants from the National University of Singapore (NUS); the Oncology Research Institute, National University Medical Institute (NUMI), Singapore; and a grant from the Academic Research Fund, Faculty of Medicine, NUS, Singapore. This work was supported by Amgen, Inc., the National Cancer Institute of Canada, and the Canadian Institute of Health Research (R.H.).
