Synthetic lethality between PAXX and XLF in mammalian development.
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Peer-reviewed
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Abstract
PAXX was identified recently as a novel nonhomologous end-joining DNA repair factor in human cells. To characterize its physiological roles, we generated Paxx-deficient mice. Like Xlf-/- mice, Paxx-/- mice are viable, grow normally, and are fertile but show mild radiosensitivity. Strikingly, while Paxx loss is epistatic with Ku80, Lig4, and Atm deficiency, Paxx/Xlf double-knockout mice display embryonic lethality associated with genomic instability, cell death in the central nervous system, and an almost complete block in lymphogenesis, phenotypes that closely resemble those of Xrcc4-/- and Lig4-/- mice. Thus, combined loss of Paxx and Xlf is synthetic-lethal in mammals.
Description
Keywords
ATM, NHEJ, PAXX, XLF, development, synthetic lethality, Animals, Apoptosis, DNA-Binding Proteins, Embryonic Development, Epistasis, Genetic, Genomic Instability, Mice, Mice, Inbred C57BL, Mice, Knockout, Protein Kinases, Radiation Tolerance, Synthetic Lethal Mutations, Trisaccharides
Journal Title
Genes Dev
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Journal ISSN
0890-9369
1549-5477
1549-5477
Volume Title
30
Publisher
Cold Spring Harbor Laboratory
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Sponsorship
Cancer Research UK (18796)
Wellcome Trust (092096/Z/10/Z)
Cancer Research Uk (None)
Cancer Research Uk (None)
Wellcome Trust (092096/Z/10/Z)
Cancer Research Uk (None)
Cancer Research Uk (None)
Research in S.P.J.’s laboratory is funded by Cancer Research UK (CRUK) program grant number C6/A11224, the European Research Council, and the European Community Seventh Framework Programme grant agreement number HEALTH-F2-2010-259893 (DDResponse). Core funding is provided by CRUK (C6946/A14492) and the Wellcome Trust (WT092096). S.P.J. receives his salary from the University of Cambridge, UK, supplemented by CRUK. L.D.’s laboratory is funded by the Institut Pasteur as well as the European Research Council (ERC) under starting grant agreement number 310917. D.J.A.’s laboratory is supported by CRUK and the Wellcome Trust. A.N.B. is supported by a CRUK Career Development Fellowship (C29215/A20772).