Histone H2AX deficiency causes neurobehavioral deficits and impaired redox homeostasis
Open accessAbstract
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.
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H2AX deficiency has been linked to chronic neurobehavioral symptoms and an impaired ability to respond to ROS.
“H2AX deficiency has also been linked to chronic neurobehavioral symptoms and an impaired ability to respond to ROS [167]”
From DNA repair deficiency and senescence in concussed professional athletes involved in contact sports (2019) · cites this paper as [167]
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References 44 · Cited by 37
- Authors
- Weyemi, U., Paul, B. D., Snowman, A. M., Jailwala, P., Nussenzweig, A., Bonner, W. M., & Snyder, S. H.
- Affiliations
- Johns Hopkins University (US)
- National Cancer Institute (US)
- National Institutes of Health (US)
- Corresponding author
- Snyder, Solomon H.
- Venue
- Nature Communications
- Published
- 2018-04-18
- Volume
- 9
- Issue
- 1
- Pages
- 1526-1526
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5906610
- OpenAlex
- W2799949272
- Cited by
- 37
- References
- 44
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 3 · 2023: 1 · 2022: 7 · 2021: 8 · 2020: 4 · 2019: 6 · 2018: 3
- FWCI
- 1.87
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Johns Hopkins University
- National Institutes of Health (MH18501, DA-000266)
- U.S. Public Health Service (DA-000266, MH‐18501)
- National Institute of Mental Health (R01MH018501, R37MH018501)
- National Institute on Drug Abuse (P50DA000266)
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Keywords
- histone H2AX, ATM kinase, reactive oxygen species, oxidative stress, redox homeostasis, neurobehavioral deficits, motor learning, balance, N-acetylcysteine, Nrf2, GCLC, NQO1, striatum, DNA repair, histone variants
- MeSH terms
- Acetylcysteine, Animals, Antioxidants, Behavior, Animal, Corpus Striatum, DNA Damage, Fibroblasts, Heterozygote, Histones, Humans, Models, Neurological, Motor Skills, Oxidation-Reduction, Phenotype, Phosphorylation, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, Microscopy, Confocal, NF-E2-Related Factor 2, Mice, HEK293 Cells
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