title: Synthetic lethality between PAXX and XLF in mammalian development.
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.
authors: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, United Kingdom.|Wellcome Trust Sanger Institute, Cambridge CB10 1HH, United Kingdom.
authors: Gabriel
authors: G
authors: Balmus
authors: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, United Kingdom.|Wellcome Trust Sanger Institute, Cambridge CB10 1HH, United Kingdom.
authors: Ana C
authors: AC
authors: Barros
authors: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, United Kingdom.|Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom.
authors: Paul W G
authors: PW
authors: Wijnhoven
authors: Department of Immunology, University of Cambridge, Cambridge CB2 1GA, United Kingdom.|Department of Genomes and Genetics, Institut Pasteur, 75015 Paris, France.
authors: Chloé
authors: C
authors: Lescale
authors: Department of Immunology, University of Cambridge, Cambridge CB2 1GA, United Kingdom.|Department of Genomes and Genetics, Institut Pasteur, 75015 Paris, France.
authors: Hélène Lenden
authors: HL
authors: Hasse
authors: Wellcome Trust Sanger Institute, Cambridge CB10 1HH, United Kingdom.
authors: Katharina
authors: K
authors: Boroviak
authors: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, United Kingdom.
authors: Carlos
authors: C
authors: le Sage
authors: Wellcome Trust Sanger Institute, Cambridge CB10 1HH, United Kingdom.
authors: Brendan
authors: B
authors: Doe
authors: Wellcome Trust Sanger Institute, Cambridge CB10 1HH, United Kingdom.
authors: Anneliese O
authors: AO
authors: Speak
authors: Wellcome Trust Sanger Institute, Cambridge CB10 1HH, United Kingdom.
authors: Antonella
authors: A
authors: Galli
authors: AstraZeneca, Cambridge CB4 0FZ, United Kingdom.
authors: Matt
authors: M
authors: Jacobsen
authors: Department of Immunology, University of Cambridge, Cambridge CB2 1GA, United Kingdom.|Department of Genomes and Genetics, Institut Pasteur, 75015 Paris, France.
authors: Ludovic
authors: L
authors: Deriano
authors: Wellcome Trust Sanger Institute, Cambridge CB10 1HH, United Kingdom.
authors: David J
authors: DJ
authors: Adams
authors: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, United Kingdom.|Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom.|Cancer Research UK/Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom.
authors: Andrew N
authors: http://orcid.org/0000-0003-1979-021X
authors: AN
authors: Blackford
authors: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, United Kingdom.|Wellcome Trust Sanger Institute, Cambridge CB10 1HH, United Kingdom.|Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom.
authors: Stephen P
authors: SP
authors: Jackson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics*; D004843:Epistasis, Genetic; D042822:Genomic Instability / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics; D000072020:Synthetic Lethal Mutations / Q000235:genetics*; D014312:Trisaccharides / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D014312:Trisaccharides; C519508:XLF protein, mouse; C066379:O-(5-O-(4-coumaroyl)-alpha-arabinofuranosyl)-(1-3)-O-beta-xylopyranosyl-(1-4)-xylopyranose; D011494:Protein Kinases
keywords: ATM; NHEJ; PAXX; XLF; development; synthetic lethality