Mitochondrial reactive oxygen species are scavenged by Cockayne syndrome B protein in human fibroblasts without nuclear DNA damage

James E. Cleaver, Angela M. Brennan-Minnella, Raymond A. Swanson, Ka Wing Fong, Junjie Chen, Kai Ming Chou, Yih Wen Chen, Ingrid Revet, Vladimir Bezrookove

Research output: Contribution to journalArticlepeer-review

55 Scopus citations


Cockayne syndrome (CS) is a human DNA repair-deficient disease that involves transcription coupled repair (TCR), in which three gene products, Cockayne syndrome A (CSA), Cockayne syndrome B (CSB), and ultraviolet stimulated scaffold protein A (UVSSA) cooperate in relieving RNA polymerase II arrest at damaged sites to permit repair of the template strand. Mutation of any of these three genes results in cells with increased sensitivity to UV light and defective TCR. Mutations in CSA or CSB are associated with severe neurological disease but mutations in UVSSA are for the most part only associated with increased photosensitivity. This difference raises questions about the relevance of TCR to neurological disease in CS. We find that CSB-mutated cells, but not UVSSA-deficient cells, have increased levels of intramitochondrial reactive oxygen species (ROS), especially when mitochondrial complex I is inhibited by rotenone. Increased ROS would result in oxidative damage to mitochondrial proteins, lipids, and DNA. CSB appears to behave as an electron scavenger in the mitochondria whose absence leads to increased oxidative stress. Mitochondrial ROS, however, did not cause detectable nuclear DNA damage even when base excision repair was blocked by an inhibitor of polyADP ribose polymerase. Neurodegeneration in Cockayne syndrome may therefore be associated with ROS-induced damage in the mitochondria, independent of nuclear TCR. An implication of our present results is that mitochondrial dysfunction involving ROS has a major impact on CS-B pathology, whereas nuclear TCR may have a minimal role.

Original languageEnglish
Pages (from-to)13487-13492
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number37
StatePublished - Sep 16 2014


  • Bromate
  • Comet assay
  • Hydrogen peroxide
  • Oxidative DNA damage
  • γH2Ax

ASJC Scopus subject areas

  • General


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