In two companion papers published in Cell Reports (27601299) and Genes & Development (27798842), the Deriano lab at the Institut Pasteur Paris and the Jackson lab at the University of Cambridge UK reveal the functions of PAXX (PAralog of XLF and XRCC4), a novel DNA repair factor, during antigen receptor assembly, lymphocyte development and mammalian development.
Specific Roles of XRCC4 Paralogs PAXX and XLF during V(D)J Recombination (Cell Rep. 2016 Sep 13;16(11):2967-79.)
Developing lymphocytes rely on nonhomologous end joining (NHEJ) to repair programmed DNA double-strand breaks generated during antigen receptor gene assembly. Deficiency in NHEJ factors results in severe combined immunodeficiency and predisposition to cancer, thus highlighting the importance of identifying all players in this process and deciphering their functions. In this study, Chloé Lescale, Hélène Lenden Hasse, et al. show that PAXX—a component of the NHEJ machinery—has a key role in V(D)J recombination that is masked by functional redundancy with its paralog XLF.
Synthetic lethality between PAXX and XLF in mammalian development (Genes Dev. 2016 Oct 1;30(19):2152-2157.)
PAXX was identified recently as a novel nonhomologous end-joining DNA repair factor in human cells. To characterize its physiological roles, Balmus et al. 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.