Blinded by the UV light: how the focus on transcription-coupled NER has distracted from understanding the mechanisms of Cockayne syndrome neurologic disease

DNA Repair (Amst). 2013 Aug;12(8):656-71. doi: 10.1016/j.dnarep.2013.04.018. Epub 2013 May 16.


Cockayne syndrome (CS) is a devastating neurodevelopmental disorder, with growth abnormalities, progeriod features, and sun sensitivity. CS is typically considered to be a DNA repair disorder, since cells from CS patients have a defect in transcription-coupled nucleotide excision repair (TC-NER). However, cells from UV-sensitive syndrome patients also lack TC-NER, but these patients do not suffer from the neurologic and other abnormalities that CS patients do. Also, the neurologic abnormalities that affect CS patients (CS neurologic disease) are qualitatively different from those seen in NER-deficient XP patients. Therefore, the TC-NER defect explains the sun sensitive phenotype common to both CS and UVsS, but cannot explain CS neurologic disease. However, as CS neurologic disease is of much greater clinical significance than the sun sensitivity, there is a pressing need to understand its molecular basis. While there is evidence for defective repair of oxidative DNA damage and mitochondrial abnormalities in CS cells, here I propose that the defects in transcription by both RNA polymerases I and II that have been documented in CS cells provide a better explanation for many of the severe growth and neurodevelopmental defects in CS patients than defective DNA repair. The implications of these ideas for interpreting results from mouse models of CS, and for the development of treatments and therapies for CS patients are discussed.

Keywords: Aging; Calcification; Demyelination; Developmental disorders; Leukodystrophy; Neurodegeration; Rare disease; Vasculopathy.

Publication types

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

MeSH terms

  • Animals
  • Cockayne Syndrome / genetics*
  • Cockayne Syndrome / pathology
  • DNA Damage
  • DNA Repair*
  • DNA Repair-Deficiency Disorders / genetics
  • DNA Repair-Deficiency Disorders / pathology
  • Disease Models, Animal
  • Humans
  • Mice
  • Oxidative Stress
  • RNA Polymerase I / genetics
  • RNA Polymerase I / metabolism
  • RNA Polymerase II / genetics
  • RNA Polymerase II / metabolism
  • Transcription, Genetic
  • Ultraviolet Rays / adverse effects*
  • Xeroderma Pigmentosum / genetics
  • Xeroderma Pigmentosum / pathology


  • RNA Polymerase II
  • RNA Polymerase I