Reports

Involvement of Mammalian Mus81 in Genome Integrity and Tumor Suppression

John Peter McPherson,^1,2* Bénédicte Lemmers,^1,2 Richard Chahwan,^1,2 Ashwin Pamidi,^1,2 Eva Migon,^1,2 Elzbieta Matysiak-Zablocki,^1,2 Mary Ellen Moynahan,³ Jeroen Essers,⁴ Katsuhiro Hanada,⁴ Anuradha Poonepalli,⁵ Otto Sanchez-Sweatman,² Rama Khokha,² Roland Kanaar,⁴ Maria Jasin,³ M. Prakash Hande,⁵ Razqallah Hakem^1,2

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 -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.

¹ Ontario Cancer Institute, 620 University Avenue, Suite 706, Toronto, Ontario, Canada M5G 2C1.
² Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 2M9.
³ Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
⁴ Department of Cell Biology and Genetics, and Department of Radiation Oncology, Erasmus MC (University Medical Center), Post Office Box 1738, 3000 DR Rotterdam, Netherlands.
⁵ Department of Physiology and Oncology Research Institute, Faculty of Medicine, National University of Singapore, Singapore 117597.

^* Present address: Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.

To whom correspondence should be addressed. E-mail: rhakem{at}uhnres.utoronto.ca

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Cleavage mechanism of human Mus81-Eme1 acting on Holliday-junction structures.

E. R. Taylor and C. H. McGowan (2008)
PNAS 105, 3757-3762
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Processing of a Psoralen DNA Interstrand Cross-link by XPF-ERCC1 Complex in Vitro.

L. A. Fisher, M. Bessho, and T. Bessho (2008)
J. Biol. Chem. 283, 1275-1281
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Human Mus81 and FANCB independently contribute to repair of DNA damage during replication.

Y. Nomura, N. Adachi, and H. Koyama (2007)
Genes Cells 12, 1111-1122
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Functional Interplay of p53 and Mus81 in DNA Damage Responses and Cancer.

A. Pamidi, R. Cardoso, A. Hakem, E. Matysiak-Zablocki, A. Poonepalli, L. Tamblyn, B. Perez-Ordonez, M. P. Hande, O. Sanchez, and R. Hakem (2007)
Cancer Res. 67, 8527-8535
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Synthetic Lethality of Drosophila in the Absence of the MUS81 Endonuclease and the DmBlm Helicase Is Associated With Elevated Apoptosis.

K. Trowbridge, K. McKim, S. J. Brill, and J. Sekelsky (2007)
Genetics 176, 1993-2001
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Two Alternatively Spliced Transcripts Generated from OsMUS81, a Rice Homolog of Yeast MUS81, Are Up-Regulated by DNA-Damaging Treatments.

N. Mimida, H. Kitamoto, K. Osakabe, M. Nakashima, Y. Ito, W.-D. Heyer, S. Toki, and H. Ichikawa (2007)
Plant Cell Physiol. 48, 648-654
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Perturbations of Vascular Homeostasis and Aortic Valve Abnormalities in Fibulin-4 Deficient Mice.

K. Hanada, M. Vermeij, G. A. Garinis, M. C. de Waard, M. G.S. Kunen, L. Myers, A. Maas, D. J. Duncker, C. Meijers, H. C. Dietz, et al. (2007)
Circ. Res. 100, 738-746
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The role of AtMUS81 in DNA repair and its genetic interaction with the helicase AtRecQ4A.

F. Hartung, S. Suer, T. Bergmann, and H. Puchta (2006)
Nucleic Acids Res. 34, 4438-4448
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Haploinsufficiency of the Mus81-Eme1 endonuclease activates the intra-S-phase and G2/M checkpoints and promotes rereplication in human cells.

T. Hiyama, M. Katsura, T. Yoshihara, M. Ishida, A. Kinomura, T. Tonda, T. Asahara, and K. Miyagawa (2006)
Nucleic Acids Res. 34, 880-892
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The Rad50S allele promotes ATM-dependent DNA damage responses and suppresses ATM deficiency: implications for the Mre11 complex as a DNA damage sensor.

M. Morales, J.-W. F. Theunissen, C. F. B. Kim, R. Kitagawa, M. B. Kastan, and J. H.J. Petrini (2005)
Genes & Dev. 19, 3043-3054
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Tumor suppressor genetics.

S. R. Payne and C. J. Kemp (2005)
Carcinogenesis 26, 2031-2045
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Disruption of Murine Mus81 Increases Genomic Instability and DNA Damage Sensitivity but Does Not Promote Tumorigenesis.

N. Dendouga, H. Gao, D. Moechars, M. Janicot, J. Vialard, and C. H. McGowan (2005)
Mol. Cell. Biol. 25, 7569-7579
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Replication checkpoint kinase Cds1 regulates Mus81 to preserve genome integrity during replication stress.

M. Kai, M. N. Boddy, P. Russell, and T. S.-F. Wang (2005)
Genes & Dev. 19, 919-932
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BLM Helicase Facilitates Mus81 Endonuclease Activity in Human Cells.

R. Zhang, S. Sengupta, Q. Yang, S. P. Linke, N. Yanaihara, J. Bradsher, V. Blais, C. H. McGowan, and C. C. Harris (2005)
Cancer Res. 65, 2526-2531
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