Synthetic lethality between PAXX and XLF in mammalian development
- Gabriel Balmus1,2,
- Ana C. Barros1,2,
- Paul W.G. Wijnhoven1,3,
- Chloé Lescale4,5,
- Hélène Lenden Hasse4,5,
- Katharina Boroviak2,
- Carlos le Sage1,9,
- Brendan Doe2,
- Anneliese O. Speak2,
- Antonella Galli2,
- Matt Jacobsen6,
- Ludovic Deriano4,5,
- David J. Adams2,
- Andrew N. Blackford1,7,8 and
- Stephen P. Jackson1,2,3
- 1Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, United Kingdom;
- 2Wellcome Trust Sanger Institute, Cambridge CB10 1HH, United Kingdom;
- 3Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom;
- 4Department of Immunology, University of Cambridge, Cambridge CB2 1GA, United Kingdom;
- 5Department of Genomes and Genetics, Institut Pasteur, 75015 Paris, France;
- 6AstraZeneca, Cambridge CB4 0FZ, United Kingdom;
- 7Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom;
- 8Cancer Research UK/Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom
- Corresponding authors: s.jackson{at}gurdon.cam.ac.uk, andrew.blackford{at}oncology.ox.ac.uk
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.
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Footnotes
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.290510.116.
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Freely available online through the Genes & Development Open Access option.
- Received July 23, 2016.
- Accepted September 21, 2016.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
