Synthetic lethality between PAXX and XLF in mammalian development.

Gabriel Balmus (1, 2) , Ana C. Barros (2, 1) , Paul W.G. Wijnhoven (3, 1) , Chloé Lescale (4, 5) , Hélène P Lenden Hasse (5, 4) , Katharina Boroviak (2) , Carlos Le Sage (1) , Brendan Doe (2) , Anneliese O. Speak (2) , Antonella Galli (2) , Matt Jacobsen (6) , Ludovic Deriano (5, 4) , David J. Adams (2) , Andrew N. Blackford (7, 1, 8) , Stephen P. Jackson (1, 2, 3)

1 Wellcome Trust/Cancer Research UK Gurdon Institute
2 The Wellcome Trust Sanger Institute [Cambridge]
3 Department of Biochemistry
4 Département de Génomes et Génétique - Department of Genomes and Genetics
5 Développement Lymphocytaire et Oncogenèse
6 AstraZeneca [Cambridge, UK]
7 University of Oxford
8 The Weatherall Institute of Molecular Medicine

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.

Keywords: ATM; NHEJ; XLF; PAXX; synthetic lethality; development

Domains: Life Sciences [q-bio]; Immunology; Adaptive immunology; Life Sciences [q-bio]; Cancer; Life Sciences [q-bio]; Biochemistry, Molecular Biology; Molecular biology

Gabriel Balmus, Ana C. Barros, Paul W.G. Wijnhoven, Chloé Lescale, Hélène P Lenden Hasse, et al.. Synthetic lethality between PAXX and XLF in mammalian development.. Genes and Development, 2016, 30 (19), pp.2152 - 2157. ⟨10.1101/gad.290510.116⟩. ⟨pasteur-01416628⟩