[en] Mammalian Exonuclease 1 (EXO1) is an evolutionarily conserved, multifunctional exonuclease involved in DNA damage repair, replication, immunoglobulin diversity, meiosis, and telomere maintenance. It has been assumed that EXO1 participates in these processes primarily through its exonuclease activity, but recent studies also suggest that EXO1 has a structural function in the assembly of higher-order protein complexes. To dissect the enzymatic and nonenzymatic roles of EXO1 in the different biological processes in vivo, we generated an EXO1-E109K knockin (Exo1(EK)) mouse expressing a stable exonuclease-deficient protein and, for comparison, a fully EXO1-deficient (Exo1(null)) mouse. In contrast to Exo1(null/null) mice, Exo1(EK/EK) mice retained mismatch repair activity and displayed normal class switch recombination and meiosis. However, both Exo1-mutant lines showed defects in DNA damage response including DNA double-strand break repair (DSBR) through DNA end resection, chromosomal stability, and tumor suppression, indicating that the enzymatic function is required for those processes. On a transformation-related protein 53 (Trp53)-null background, the DSBR defect caused by the E109K mutation altered the tumor spectrum but did not affect the overall survival as compared with p53-Exo1(null) mice, whose defects in both DSBR and mismatch repair also compromised survival. The separation of these functions demonstrates the differential requirement for the structural function and nuclease activity of mammalian EXO1 in distinct DNA repair processes and tumorigenesis in vivo.
Disciplines :
Immunology & infectious disease
Author, co-author :
Schaetzlein, Sonja; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
CHAHWAN, Richard ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Health, Medicine and Life Sciences (DHML) ; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, United States
Avdievich, Elena; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, United States
Roa, Sergio; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, United States ; Oncology Division, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain
Wei, Kaichun; Department of Obstetrics and Gynecology, University of Missouri, Kansas City, MO 64108, United States
Eoff, Robert L; Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States
Sellers, Rani S; Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, United States
Clark, Alan B; Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, United States ; Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, United States
Kunkel, Thomas A; Laboratory of Molecular Genetics and ; Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709
Scharff, Matthew D; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, United States
Edelmann, Winfried; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, United States
External co-authors :
yes
Language :
English
Title :
Mammalian Exo1 encodes both structural and catalytic functions that play distinct roles in essential biological processes.
Publication date :
02 July 2013
Journal title :
Proceedings of the National Academy of Sciences of the United States of America
ISSN :
0027-8424
eISSN :
1091-6490
Publisher :
Proceedings of the National Academy of Sciences, United States
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