A Critical Role for DNA End-Joining Proteins in Both Lymphogenesis and Neurogenesis

Abstract

XRCC4 was identified via a complementation cloning method that employed an ionizing radiation (IR)-sensitive hamster cell line. By gene-targeted mutation, we show that XRCC4 deficiency in primary murine cells causes growth defects, premature senescence, IR sensitivity, and inability to support V(D)J recombination. In mice, XRCC4 deficiency causes late embryonic lethality accompanied by defective lymphogenesis and defective neurogenesis manifested by extensive apoptotic death of newly generated postmitotic neuronal cells. We find similar neuronal developmental defects in embryos that lack DNA ligase IV, an XRCC4-associated protein. Our findings demonstrate that differentiating lymphocytes and neurons strictly require the XRCC4 and DNA ligase IV end-joining proteins and point to the general stage of neuronal development in which these proteins are necessary.

Roles for NF-κB in nerve cell survival, plasticity, and disease

“…89,90 In addition, several studies have documented increased amounts of DNA damage in vulnerable neuronal populations in both patients and animal models of Alzheimer's, Parkinson's, Huntington's diseases, and stroke. 91 Activation of NF-kB by DNA damage can occur through multiple pathways, including both p53-independent and p53-dependent signaling mechanisms.…”

DNA double-strand break repair and development

“…Xrcc4 À/À and Lig4 À/À mice are virtually identical in phenotype, and in contrast to the viability of DNA-PK-deficient mice, are embryonic lethal, presumably due to abundant apoptosis of newly postmitotic neurons (Barnes et al, 1998;Frank et al, 1998;Gao et al, 1998b). Like other NHEJ-deficient models, Xrcc4 À/À and Lig4 À/À embryos also showed impaired V(D)J recombination and embryonic fibroblasts exhibited IR sensitivity and premature senescence (Frank et al, 1998;Gao et al, 1998b). Ku70 À/À and Ku80 À/À mice, while viable, likewise showed increased apoptosis in post-mitotic neural cells, though to a lesser extent than seen in Xrcc4 À/À and Lig4 À/À embryos (Gu et al, 2000).…”

“…The extent to which Artemis is required during canonical NHEJ (independent of V(D)J recombination) remains uncertain, as conflicting data on its requirement for end joining have been reported (Rooney et al, 2003;Riballo et al, 2004;Zhang et al, 2004;Wang et al, 2005b). However, Lig4 and Xrcc4 are essential for NHEJ and embryonic survival (Barnes et al, 1998;Frank et al, 1998;Gao et al, 1998b), and their interaction is required for efficient end joining as Lig4 is not sufficient to complete repair in the absence of Xrcc4 (Critchlow et al, 1997;Grawunder et al, 1997Grawunder et al, , 1998aBassing and Alt, 2004). While HR is available for repair during late S/G 2 , NHEJ is most prominently activated in G 1 , G 0 and early S phase of the cell cycle (Rothkamm et al, 2003;Thacker and Zdzienicka, 2004).…”

Non-homologous end-joining, a sticky affair

“…NHEJ efficiency is minimal in the absence of this complex and a defect in ligase IV or XRCC4 is even lethal in mice (Barnes et al, 1998;Frank et al, 1998;Gao et al, 1998b). XRCC4 is absolutely required for ligase IV activity, probably because the ligase IV protein needs it for stability and correct targeting to DSBs (Grawunder et al, 1997;Bryans et al, 1999;Chen et al, 2000;Teo and Jackson, 2000;Hsu et al, 2002;Drouet et al, 2005;Costantini et al, 2007).…”