Journal
GENES & DEVELOPMENT
Volume 23, Issue 2, Pages 171-180Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1746609
Keywords
NBS; ATLD; A-T; DNA damage; neurodegeneration
Categories
Funding
- National Institutes of Health (NIH) [NS-37956, CA-21765]
- CCSG [P30 CA21765]
- American Lebanese and Syrian Associated Charities (ALSAC) of St. Jude Children's Research Hospital
- Joel and Jean Smilow Initiative
- Leukemia and Lymphoma Society
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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(Delta B/Delta B) 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(Delta B/Delta B) 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(Delta B/Delta B), 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.
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