Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

Science 18 June 2004:
Vol. 304. no. 5678, pp. 1822 - 1826
DOI: 10.1126/science.1094557
Prev | Table of Contents | Next

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 Hakem1,2{dagger}

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.

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.

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

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Two Distinct MUS81-EME1 Complexes from Arabidopsis Process Holliday Junctions.
V. Geuting, D. Kobbe, F. Hartung, J. Durr, M. Focke, and H. Puchta (2009)
Plant Physiology 150, 1062-1071
   Abstract »    Full Text »    PDF »
Human Rad54 protein stimulates human Mus81-Eme1 endonuclease.
O. M. Mazina and A. V. Mazin (2008)
PNAS 105, 18249-18254
   Abstract »    Full Text »    PDF »
Replication fork stalling in WRN-deficient cells is overcome by prompt activation of a MUS81-dependent pathway.
A. Franchitto, L. M. Pirzio, E. Prosperi, O. Sapora, M. Bignami, and P. Pichierri (2008)
J. Cell Biol. 183, 241-252
   Abstract »    Full Text »    PDF »
Deconstructing meiosis one kinase at a time: polo pushes past pachytene.
N. M. Hollingsworth (2008)
Genes & Dev. 22, 2596-2600
   Abstract »    Full Text »    PDF »
Cleavage mechanism of human Mus81-Eme1 acting on Holliday-junction structures.
E. R. Taylor and C. H. McGowan (2008)
PNAS 105, 3757-3762
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Tumor suppressor genetics.
S. R. Payne and C. J. Kemp (2005)
Carcinogenesis 26, 2031-2045
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)