Histone H2AX deficiency causes neurobehavioral deficits and impaired redox homeostasis

Urbain Weyemi,Bindu D Paul,Parthav Jailwala,Solomon H Snyder,William M Bonner,Adele M Snowman,Andre Nussenzweig

doi:10.1038/s41467-018-03948-9

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.

Highlights

ATM drives DNA repair by phosphorylating the histone variant H2AX
Chen et al recently depicted the role of ATM in redox homeostasis, showing that ATM activation by oxidative stress leads to a transcriptional program that includes IL-8, during progression of primary tumors into metastatic nodules[14]
Ataxia Telangiectasia patients display defects in motor activity associated with cerebellar abnormalities including diminished Purkinje and granule cell populations

Summary

Introduction

ATM drives DNA repair by phosphorylating the histone variant H2AX. While ATM mutations elicit prominent neurobehavioral phenotypes, neural roles for H2AX have been elusive. H2AX plays essential roles in DNA double-strand break repair and genome stability, and is classified as a tumor suppressor[6]. While ATM is best known for its function in DNA repair, it mediates cellular reactive oxygen species (ROS) homeostasis[13]. Similarities between ATM and the histone variant H2AX are evident in the phenotypes of their knockout mouse models. In both instances males are sterile, and there is genomic instability evidenced by abnormalities in chromosome structure, immunodeficiency, and enhanced radiosensitivity. These similarities most likely reflect their common roles in DNA repair. H2AX mediates physiologic responses to oxidative stress through NRF2transcriptional targets, and antioxidant treatment ameliorates the neurobehavioral deficits of H2AX mutants

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Conclusion