Differential DNA damage signaling accounts for distinct neural apoptotic responses in ATLD and NBS Journal Article
| Authors: | Shull, E. R. P.; Lee, Y.; Nakane, H.; Stracker, T. H.; Zhao, J.; Russell, H. R.; Petrini, J. H. J.; McKinnon, P. J. |
| Article Title: | Differential DNA damage signaling accounts for distinct neural apoptotic responses in ATLD and NBS |
| Abstract: | The MRN complex (Mre11/RAD50/NBS1) and ATM (ataxia telangiectasia, mutated) are critical for the cellular response to DNA damage. ATM disruption causes ataxia telangiectasia (A-T), while MRN dysfunction can lead to A-T-like disease (ATLD) or Nijmegen breakage syndrome (NBS). Neuropathology is a hallmark of these diseases, whereby neurodegeneration occurs in A-T and ATLD while microcephaly characterizes NBS. To understand the contrasting neuropathology resulting from Mre11 or Nbs1 hypomorphic mutations, we analyzed neural tissue from Mre11<sup>ATLD1/ATLD1</sup> and Nbs1<sup>ΔB/ΔB</sup> mice after genotoxic stress. We found a pronounced resistance to DNA damage-induced apoptosis after ionizing radiation or DNA ligase IV (Lig4) loss in the Mre11<sup>ATLD1/ATLD1</sup> nervous system that was associated with defective Atm activation and phosphorylation of its substrates Chk2 and p53. Conversely, DNA damage-induced Atm phosphorylation was defective in Nbs1 <sup>ΔB/ΔB</sup> neural tissue, although apoptosis occurred normally. We also conditionally disrupted Lig4 throughout the nervous system using Nestin-cre (Lig4<sup>Nes-Cre</sup>), and while viable, these mice showed pronounced microcephaly and a prominent age-related accumulation of DNA damage throughout the brain. Either Atm<sup>-/-</sup> or Mre11<sup>ATLD1/ATLD1</sup> genetic backgrounds, but not Nbs1<sup>ΔB/ΔB</sup>, rescued Lig4 <sup>Nes-Cre</sup> microcephaly. Thus, DNA damage signaling in the nervous system is different between ATLD and NBS and likely explains their respective neuropathology. © 2009 by Cold Spring Harbor Laboratory Press. |
| Keywords: | signal transduction; controlled study; protein phosphorylation; unclassified drug; gene mutation; mutation; dna-binding proteins; nonhuman; animal cell; mouse; animals; cell cycle proteins; mice; mre11 protein; animal tissue; dna damage; mus; apoptosis; embryo; animal experiment; animal model; protein; neurons; enzyme activation; mice, transgenic; nibrin; nuclear proteins; brain; protein-serine-threonine kinases; tumor suppressor proteins; atm protein; ionizing radiation; dna repair enzymes; radiation, ionizing; nijmegen breakage syndrome; polydeoxyribonucleotide synthase; cre recombinase; neuropathology; genotoxicity; dna ligases; a-t; atld; nbs; neurodegeneration; lig4 protein; ataxia telangiectasia; microcephaly; nervous system; nes |
| Journal Title: | Genes and Development |
| Volume: | 23 |
| Issue: | 2 |
| ISSN: | 0890-9369 |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Date Published: | 2009-01-15 |
| Start Page: | 171 |
| End Page: | 180 |
| Language: | English |
| DOI: | 10.1101/gad.1746609 |
| PUBMED: | 19171781 |
| PROVIDER: | scopus |
| PMCID: | PMC2648541 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 4" - "Export Date: 30 November 2010" - "CODEN: GEDEE" - "Source: Scopus" |
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