Superoxide dismutase 1 acts as a nuclear transcription factor to regulate oxidative stress resistance

Nat Commun. 2014 Mar 19;5:3446. doi: 10.1038/ncomms4446.

Abstract

Superoxide dismutase 1 (Sod1) has been known for nearly half a century for catalysis of superoxide to hydrogen peroxide. Here we report a new Sod1 function in oxidative signalling: in response to elevated endogenous and exogenous reactive oxygen species (ROS), Sod1 rapidly relocates into the nucleus, which is important for maintaining genomic stability. Interestingly, H2O2 is sufficient to promote Sod1 nuclear localization, indicating that it is responding to general ROS rather than Sod1 substrate superoxide. ROS signalling is mediated by Mec1/ATM and its effector Dun1/Cds1 kinase, through Dun1 interaction with Sod1 and regulation of Sod1 by phosphorylation at S60, 99. In the nucleus, Sod1 binds to promoters and regulates the expression of oxidative resistance and repair genes. Altogether, our study unravels an unorthodox function of Sod1 as a transcription factor and elucidates the regulatory mechanism for its localization.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Active Transport, Cell Nucleus
  • Blotting, Western
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Nucleus / metabolism*
  • Fibroblasts / cytology
  • Fibroblasts / enzymology
  • Fibroblasts / metabolism
  • Gene Expression Regulation, Fungal / drug effects
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Microscopy, Fluorescence
  • Mutation
  • Oligonucleotide Array Sequence Analysis
  • Oxidants / pharmacology
  • Oxidative Stress*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Reactive Oxygen Species / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism*
  • Superoxide Dismutase-1
  • Superoxides / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptome / drug effects
  • Transcriptome / genetics

Substances

  • Cell Cycle Proteins
  • Intracellular Signaling Peptides and Proteins
  • Oxidants
  • Reactive Oxygen Species
  • SOD1 protein, human
  • Saccharomyces cerevisiae Proteins
  • Transcription Factors
  • Superoxides
  • Hydrogen Peroxide
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • DUN1 protein, S cerevisiae
  • MEC1 protein, S cerevisiae
  • Protein-Serine-Threonine Kinases

Associated data

  • GEO/GSE55081