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Differential DNA damage signaling accounts for distinct neural apoptotic responses in ATLD and NBS.

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(ATLD1/ATLD1) and Nbs1(DeltaB/DeltaB) 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(ATLD1/ATLD1) 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(DeltaB/DeltaB) neural tissue, although apoptosis occurred normally. We also conditionally disrupted Lig4 throughout the nervous system using Nestin-cre (Lig4(Nes-Cre)), and while viable, these mice showed pronounced microcephaly and a prominent age-related accumulation of DNA damage throughout the brain. Either Atm-/- or Mre11(ATLD1/ATLD1) genetic backgrounds, but not Nbs1(DeltaB/DeltaB), rescued Lig4(Nes-Cre) microcephaly. Thus, DNA damage signaling in the nervous system is different between ATLD and NBS and likely explains their respective neuropathology.

Pubmed ID: 19171781

Authors

  • Shull ER
  • Lee Y
  • Nakane H
  • Stracker TH
  • Zhao J
  • Russell HR
  • Petrini JH
  • McKinnon PJ

Journal

Genes & development

Publication Data

January 15, 2009

Associated Grants

  • Agency: NCI NIH HHS, Id: CA-21765
  • Agency: NINDS NIH HHS, Id: NS-37956
  • Agency: NCI NIH HHS, Id: P30 CA21765
  • Agency: NIGMS NIH HHS, Id: R01 GM059413
  • Agency: NINDS NIH HHS, Id: R01 NS037956
  • Agency: NINDS NIH HHS, Id: R01 NS037956-12

Mesh Terms

  • Animals
  • Apoptosis
  • Ataxia Telangiectasia
  • Ataxia Telangiectasia Mutated Proteins
  • Brain
  • Cell Cycle Proteins
  • DNA Damage
  • DNA Ligases
  • DNA Repair Enzymes
  • DNA-Binding Proteins
  • Enzyme Activation
  • Female
  • Male
  • Mice
  • Mice, Transgenic
  • Microcephaly
  • Mutation
  • Neurons
  • Nijmegen Breakage Syndrome
  • Nuclear Proteins
  • Protein-Serine-Threonine Kinases
  • Radiation, Ionizing
  • Signal Transduction
  • Tumor Suppressor Proteins