Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA

Morten Scheibye-Knudsen, Anne Tseng, Martin Borch Jensen, Karsten Scheibye-Alsing, Evandro Fei Fang, Teruaki Iyama, Sanjay Kumar Bharti, Krisztina Marosi, Lynn Froetscher, Henok Kassahun, David Mark Eckley, Robert W. Maul, Paul Bastian, Supriyo De, Soumita Ghosh, Hilde Nilsen, Ilya G. Goldberg, Mark P. Mattson, David M. Wilson, Robert M. BroshMyriam Gorospe, Vilhelm A. Bohr

Research output: Contribution to journalArticlepeer-review


Cockayne syndrome is a neurodegenerative accelerated aging disorder caused by mutations in the CSA or CSB genes. Although the pathogenesis of Cockayne syndrome has remained elusive, recent work implicates mitochondrial dysfunction in the disease progression. Here,we present evidence that loss of CSA or CSB in a neuroblastoma cell line converges on mitochondrial dysfunction caused by defects in ribosomal DNA transcription and activation of the DNA damage sensor poly-ADP ribose polymerase 1 (PARP1). Indeed, inhibition of ribosomal DNA transcription leads to mitochondrial dysfunction in a number of cell lines. Furthermore, machine-learning algorithms predict that diseases with defects in ribosomal DNA (rDNA) transcription have mitochondrial dysfunction, and, accordingly, this is found when factors involved in rDNA transcription are knocked down. Mechanistically, loss of CSA or CSB leads to polymerase stalling at non-B DNA in a neuroblastoma cell line, in particular at G-quadruplex structures, and recombinant CSB can melt G-quadruplex structures. Indeed, stabilization of G-quadruplex structures activates PARP1 and leads to accelerated aging in Caenorhabditis elegans. In conclusion, this work supports a role for impaired ribosomal DNA transcription in Cockayne syndrome and suggests that transcription-coupled resolution of secondary structures may be a mechanism to repress spurious activation of a DNA damage response.

Original languageEnglish (US)
Pages (from-to)12502-12507
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number44
StatePublished - Nov 1 2016
Externally publishedYes


  • Aging
  • Cockayne syndrome
  • CSA
  • CSB
  • Nucleolus
  • Polymerase I transcription

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA'. Together they form a unique fingerprint.

Cite this