In:
Genes & Development, Cold Spring Harbor Laboratory, Vol. 23, No. 2 ( 2009-01-15), p. 171-180
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 ΔB/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 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 ΔB/ΔB 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 ΔB/ΔB , 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.
Type of Medium:
Online Resource
ISSN:
0890-9369
,
1549-5477
Language:
English
Publisher:
Cold Spring Harbor Laboratory
Publication Date:
2009
detail.hit.zdb_id:
1467414-2
SSG:
12
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