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

Proc Natl Acad Sci U S A. 2016 Nov 1;113(44):12502-12507. doi: 10.1073/pnas.1610198113. Epub 2016 Oct 18.

Abstract

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.

Keywords: CSA; CSB; Cockayne syndrome; aging; nucleolus; polymerase I transcription.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cockayne Syndrome / genetics
  • Cockayne Syndrome / metabolism
  • DNA Damage
  • DNA Helicases / genetics*
  • DNA Helicases / metabolism
  • DNA Repair
  • DNA Repair Enzymes / genetics*
  • DNA Repair Enzymes / metabolism
  • DNA, Neoplasm / chemistry
  • DNA, Neoplasm / genetics*
  • DNA, Neoplasm / metabolism
  • DNA, Ribosomal / genetics
  • G-Quadruplexes
  • Gene Knockdown Techniques
  • Humans
  • Neuroblastoma / genetics
  • Neuroblastoma / metabolism
  • Neuroblastoma / pathology
  • Poly (ADP-Ribose) Polymerase-1 / genetics
  • Poly (ADP-Ribose) Polymerase-1 / metabolism
  • Poly-ADP-Ribose Binding Proteins / genetics*
  • Poly-ADP-Ribose Binding Proteins / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription, Genetic*

Substances

  • DNA, Neoplasm
  • DNA, Ribosomal
  • ERCC8 protein, human
  • Poly-ADP-Ribose Binding Proteins
  • Transcription Factors
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • DNA Helicases
  • ERCC6 protein, human
  • DNA Repair Enzymes