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.
Highlights
DNA double-strand breaks (DSBs) are extremely toxic lesions that must be repaired for an organism to pass on its genetic material intact to the generation (Jackson and Bartek 2009)
Ku forms a platform for the downstream recruitment of core nonhomologous end-joining (NHEJ) factors such as DNA ligase IV (LIG4); its stable binding partner, XRCC4; and XLF, a protein structurally related to XRCC4 (Ochi et al 2014)
Loss of Xrcc4 or Lig4 results in a more severe phenotype with embryonic growth defects, blocked lymphogenesis, and late embryonic lethality associated with a large increase in cell death in the developing central nervous system (CNS) (Barnes et al 1998; Frank et al 1998; Gao et al 1998)
Summary
Xlf−/− B cells perform V(D)J recombination at almost wild-type levels, which explains the lack of significant immunodeficiency in these mice and suggests that compensatory mechanisms can mitigate loss of XLF in developing lymphocytes One of these mechanisms comprises the ATM–H2AX–53BP1 axis of DSB repair, as combined loss of any one of these factors with XLF deficiency causes profound defects in V(D)J recombination and lymphocyte development even though loss of any of these proteins individually is not significantly detrimental to these processes (Zha et al 2011; Liu et al 2012; Oksenych et al 2012). Combined loss of Paxx and Xlf is synthetic-lethal, as the majority of double-knockout embryos dies before birth with significant growth defects, increased genomic instability and subsequent cell death in the developing CNS, and an almost complete block in lymphocyte development, phenotypes that are strongly reminiscent of Xrcc4−/− or Lig4−/− mice. PAXX and XLF share a redundant function that is critical for DNA repair during mammalian development
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