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 hall...

Full description

Saved in:
Bibliographic Details
Published in:Genes & development 2009-01, Vol.23 (2), p.171-180
Main Authors: Shull, Erin R P, Lee, Youngsoo, Nakane, Hironobu, Stracker, Travis H, Zhao, Jingfeng, Russell, Helen R, Petrini, John H J, McKinnon, Peter J
Format: Article
Language:English
Subjects:
Animals
Apoptosis - radiation effects
Ataxia Telangiectasia - genetics
Ataxia Telangiectasia - physiopathology
Ataxia Telangiectasia Mutated Proteins
Brain - pathology
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
DNA Damage - genetics
DNA Damage - physiology
DNA Ligase ATP
DNA Ligases - metabolism
DNA Repair Enzymes - genetics
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Enzyme Activation - physiology
Female
Male
Mice
Mice, Transgenic
Microcephaly - pathology
MRE11 Homologue Protein
Mutation
Neurons - cytology
Neurons - physiology
Neurons - radiation effects
Nijmegen Breakage Syndrome - genetics
Nijmegen Breakage Syndrome - physiopathology
Nuclear Proteins - genetics
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Radiation, Ionizing
Research Paper
Signal Transduction - genetics
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.1746609