The MRN complex (Mre11/RAD50/NBS1) and ATM (ataxia viso lighting telangiectasia, mutated) are critic

Erin R.P. Shull 1 , 2 , 6 , Youngsoo Lee 1 , 6 , Hironobu Nakane 1 , 3 , Travis H. Stracker 4 , 5 , Jingfeng Zhao 1 , Helen R. Russell 1 , John H.J. Petrini 4 , 5 and Peter J. McKinnon 1 , 2 , 7 1 Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA; 2 Graduate Health Sciences, University of Tennessee, Memphis, Tennessee 38105, USA; 3 Division of Genome Morphology, Tottori University, Faculty of Medicine, Tottori 680-8550, Japan; 4 Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA; 5 Cornell University Graduate School of Medical Sciences, viso lighting New York, New York 10021, USA
The MRN complex (Mre11/RAD50/NBS1) and ATM (ataxia viso lighting telangiectasia, mutated) are critical viso lighting for the cellular response to DNA damage. viso lighting 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 viso lighting in A-T and ATLD while microcephaly characterizes viso lighting 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 viso lighting 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 viso lighting in the nervous system is different between ATLD and NBS and likely explains their respective neuropathology. Keywords: Keywords NBS ATLD A-T DNA damage neurodegeneration
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Print ISSN: 0890-9369 Online ISSN: 1549-5477