The ATM cofactor ATMIN protects against oxidative stress and accumulation of DNA damage in the aging brain

Nnennaya Kanu, Kay Penicud, Mariya Hristova, Barnaby Wong, Elaine Irvine, Florian Plattner, Gennadij Raivich, Axel Behrens

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Progressive accumulation of DNA damage is causally involved in cellular senescence and organismal aging. The DNA damage kinase ATM plays a central role in maintaining genomic stability. ATM mutations cause the genetic disorder ataxia telangiectasia, which is primarily characterized by progressive neurodegeneration and cancer susceptibility. Although the importance of ATM function to protect against oxidative DNA damage and during aging is well described, the mechanism of ATM activation by these stimuli is not known. Here we identify ATM interactor (ATMIN) as an essential component of the ATM signaling pathway in response to oxidative stress and aging. Embryos lacking ATMIN (atminΔ/Δ) died in utero and showed increased numbers of cells positive for phosphorylated histone H2aX, indicative of increased DNA damage. atminΔ/Δ mouse embryonic fibroblasts accumulated DNA damage and prematurely entered senescence when cultured at atmospheric oxygen levels (20%), but this defect was rescued by addition of an antioxidant and also by culturing cells at physiological oxygen levels (3%). In response to acute oxidative stress, atminΔ/N mouse embryonic fibroblasts showed slightly lower levels of ATM phosphorylation and reduced ATM substrate phosphorylation. Conditional deletion of ATMIN in the murine nervous system (atminΔN) resulted in reduced numbers of dopaminergic neurons, as does ATM deficiency. ATM activity was observed in old, but not in young, control mice, but aging-induced ATM signaling was impaired by ATMIN deficiency. Consequently, old atminΔN mice showed accumulation of DNA damage in the cortex accompanied by gliosis, resulting in increased mortality of aging mutant mice. These results suggest that ATMIN mediates ATM activation by oxidative stress, and thereby ATMIN protects the aging brain by preventing accumulation of DNA damage.

Original languageEnglish (US)
Pages (from-to)38534-38542
Number of pages9
JournalJournal of Biological Chemistry
Volume285
Issue number49
DOIs
StatePublished - Dec 3 2010

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Oxidative stress
Automatic teller machines
DNA Damage
Brain
Oxidative Stress
Aging of materials
DNA
Nervous System
Fibroblasts
Polynucleotide 5'-Hydroxyl-Kinase
Phosphorylation
Neurologic Mutant Mice
Oxygen
Ataxia Telangiectasia
Inborn Genetic Diseases
Gliosis
Genomic Instability
Cell Aging
Dopaminergic Neurons
Histones

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Kanu, N., Penicud, K., Hristova, M., Wong, B., Irvine, E., Plattner, F., ... Behrens, A. (2010). The ATM cofactor ATMIN protects against oxidative stress and accumulation of DNA damage in the aging brain. Journal of Biological Chemistry, 285(49), 38534-38542. https://doi.org/10.1074/jbc.M110.145896

The ATM cofactor ATMIN protects against oxidative stress and accumulation of DNA damage in the aging brain. / Kanu, Nnennaya; Penicud, Kay; Hristova, Mariya; Wong, Barnaby; Irvine, Elaine; Plattner, Florian; Raivich, Gennadij; Behrens, Axel.

In: Journal of Biological Chemistry, Vol. 285, No. 49, 03.12.2010, p. 38534-38542.

Research output: Contribution to journalArticle

Kanu, N, Penicud, K, Hristova, M, Wong, B, Irvine, E, Plattner, F, Raivich, G & Behrens, A 2010, 'The ATM cofactor ATMIN protects against oxidative stress and accumulation of DNA damage in the aging brain', Journal of Biological Chemistry, vol. 285, no. 49, pp. 38534-38542. https://doi.org/10.1074/jbc.M110.145896
Kanu, Nnennaya ; Penicud, Kay ; Hristova, Mariya ; Wong, Barnaby ; Irvine, Elaine ; Plattner, Florian ; Raivich, Gennadij ; Behrens, Axel. / The ATM cofactor ATMIN protects against oxidative stress and accumulation of DNA damage in the aging brain. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 49. pp. 38534-38542.
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