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Nat Commun. 2018 Apr 18;9(1):1526. doi: 10.1038/s41467-018-03948-9.

Histone H2AX deficiency causes neurobehavioral deficits and impaired redox homeostasis.

Author information

1
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
2
Center for Cancer Research Collaborative Bioinformatics Resource, National Cancer Institute, Bethesda, MD, 20892, USA.
3
Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
4
Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
5
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. ssnyder@jhmi.edu.
6
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. ssnyder@jhmi.edu.
7
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. ssnyder@jhmi.edu.

Abstract

ATM drives DNA repair by phosphorylating the histone variant H2AX. While ATM mutations elicit prominent neurobehavioral phenotypes, neural roles for H2AX have been elusive. We report impaired motor learning and balance in H2AX-deficient mice. Mitigation of reactive oxygen species (ROS) with N-acetylcysteine (NAC) reverses the behavioral deficits. Mouse embryonic fibroblasts deficient for H2AX exhibit increased ROS production and failure to activate the antioxidant response pathway controlled by the transcription factor NRF2. The NRF2 targets GCLC and NQO1 are depleted in the striatum of H2AX knockouts, one of the regions most vulnerable to ROS-mediated damage. These findings establish a role for ROS in the behavioral deficits of H2AX knockout mice and reveal a physiologic function of H2AX in mediating influences of oxidative stress on NRF2-transcriptional targets and behavior.

PMID:
29670103
PMCID:
PMC5906610
DOI:
10.1038/s41467-018-03948-9
[Indexed for MEDLINE]
Free PMC Article

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