Differential DNA damage signaling accounts for distinct neural apoptotic responses in ATLD and NBS
- Erin R.P. Shull1,2,6,
- Youngsoo Lee1,6,
- Hironobu Nakane1,3,
- Travis H. Stracker4,5,
- Jingfeng Zhao1,
- Helen R. Russell1,
- John H.J. Petrini4,5 and
- Peter J. McKinnon1,2,7
- 1Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;
- 2Graduate Health Sciences, University of Tennessee, Memphis, Tennessee 38105, USA;
- 3Division of Genome Morphology, Tottori University, Faculty of Medicine, Tottori 680-8550, Japan;
- 4Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA;
- 5Cornell University Graduate School of Medical Sciences, New York, New York 10021, USA
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↵ These authors contributed equally to this work.
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 Mre11ATLD1/ATLD1 and Nbs1ΔB/ΔB 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 Mre11ATLD1/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 Nbs1ΔB/ΔB neural tissue, although apoptosis occurred normally. We also conditionally disrupted Lig4 throughout the nervous system using Nestin-cre (Lig4Nes-Cre), and while viable, these mice showed pronounced microcephaly and a prominent age-related accumulation of DNA damage throughout the brain. Either Atm−/− or Mre11ATLD1/ATLD1 genetic backgrounds, but not Nbs1ΔB/ΔB, rescued Lig4Nes-Cre microcephaly. Thus, DNA damage signaling in the nervous system is different between ATLD and NBS and likely explains their respective neuropathology.
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Footnotes
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↵ Corresponding author.
↵ E-MAIL peter.mckinnon{at}stjude.org; FAX (901) 595-6035.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1746609.
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Supplemental material is available at http://www.genesdev.org.
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- Received September 30, 2008.
- Accepted December 2, 2008.
- Copyright © 2009 by Cold Spring Harbor Laboratory Press