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Synthetic lethality between PAXX and XLF in mammalian development.

Published version
Peer-reviewed

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Authors

Balmus, Gabriel 
Barros, Ana C 
Wijnhoven, Paul WG 
Lescale, Chloé 
Hasse, Hélène Lenden 

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

Conference Name

Journal ISSN

0890-9369
1549-5477

Volume Title

30

Publisher

Cold Spring Harbor Laboratory
Sponsorship
Cancer Research UK (18796)
Wellcome Trust (092096/Z/10/Z)
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).