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(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.
authors.affiliation: Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Erin R P
authors.initials: ER
authors.lastname: Shull
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Lee
authors.forename: Hironobu
authors.initials: H
authors.lastname: Nakane
authors.forename: Travis H
authors.initials: TH
authors.lastname: Stracker
authors.forename: Jingfeng
authors.initials: J
authors.lastname: Zhao
authors.forename: Helen R
authors.initials: HR
authors.lastname: Russell
authors.forename: John H J
authors.initials: JH
authors.lastname: Petrini
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McKinnon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D001260:Ataxia Telangiectasia / Q000235:genetics / Q000503:physiopathology*; D064007:Ataxia Telangiectasia Mutated Proteins; D001921:Brain / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics / Q000502:physiology*; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D000076228:MRE11 Homologue Protein; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008831:Microcephaly / Q000473:pathology; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000502:physiology* / Q000528:radiation effects; D049932:Nijmegen Breakage Syndrome / Q000235:genetics / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C512689:Mre11a protein, mouse; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D000076228:MRE11 Homologue Protein; D011088:DNA Ligases; D045643:DNA Repair Enzymes; D000072481:DNA Ligase ATP