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| Subject Categories: Genome Stability & Dynamics |
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| The EMBO Journal
(2003) 22, 6137–6147, doi:10.1093/emboj/cdg580 |
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| Eme1 is involved in DNA damage processing and maintenance of genomic stability in mammalian cells |
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| Jacinth Abraham1, 2, 7, Bénédicte Lemmers1, 2, 7, M.Prakash Hande3, Mary Ellen Moynahan4, Charly Chahwan1, Alberto Ciccia5, Jeroen Essers6, Katsuhiro Hanada6, Richard Chahwan1, Aik Kia Khaw3, Peter McPherson1, Amro Shehabeldin1, 2, Rob Laister2, Cheryl Arrowsmith2, Roland Kanaar6, Stephen C. West5, Maria Jasin4 and Razqallah Hakem1, 2 |
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1 Advanced Medical Discovery Institute, Ontario Cancer Institute, 620 University Avenue, Suite 706, Toronto, Ontario M5G 2C1, Canada 2 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada 3 Faculty of Medicine, National University of Singapore, Singapore 117597, USA 4 Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA 5 Cancer Research UK, London Research Institute, Clare Hall Laboratories, South Mimms, Herts EN6 3LD, UK 6 Department of Cell Biology and Genetics, and Department of Radiation Oncology, Erasmus MC, PO Box 1738, 3000 DR Rotterdam, The Netherlands 7 J.Abraham and B.Lemmers contributed equally to this work To whom correspondence should be addressed Razqallah Hakem, rhakem@uhnres.utoronto.ca Received 9 April 2003; Revised 20 August 2003; Accepted 25 September 2003. |
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| Abstract |
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| Yeast and human Eme1 protein, in complex with Mus81, constitute an endonuclease that cleaves branched DNA structures, especially those arising during stalled DNA replication. We identified mouse Eme1, and show that it interacts with Mus81 to form a complex that preferentially cleaves 3'-flap structures and replication forks rather than Holliday junctions in vitro. We demonstrate that Eme1-/- embryonic stem (ES) cells are hypersensitive to the DNA cross-linking agents mitomycin C and cisplatin, but only mildly sensitive to ionizing radiation, UV radiation and hydroxyurea treatment. Mammalian Eme1 is not required for the resolution of DNA intermediates that arise during homologous recombination processes such as gene targeting, gene conversion and sister chromatid exchange (SCE). Unlike Blm-deficient ES cells, increased SCE was seen only following induced DNA damage in Eme1-deficient cells. Most importantly, Eme1 deficiency led to spontaneous genomic instability. These results reveal that mammalian Eme1 plays a key role in DNA repair and the maintenance of genome integrity. |
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| Keywords: DNA repair, genomic instability, homologous recombination, inter-strand DNA cross-links, Mus81–Eme1 |
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