The conserved Cockayne syndrome B-piggyBac fusion protein (CSB-PGBD3) affects DNA repair and induces both interferon-like and innate antiviral responses in CSB-null cells

DNA Repair (Amst). 2012 May 1;11(5):488-501. doi: 10.1016/j.dnarep.2012.02.004. Epub 2012 Apr 6.


Cockayne syndrome is a segmental progeria most often caused by mutations in the CSB gene encoding a SWI/SNF-like ATPase required for transcription-coupled DNA repair (TCR). Over 43Mya before marmosets diverged from humans, a piggyBac3 (PGBD3) transposable element integrated into intron 5 of the CSB gene. As a result, primate CSB genes now generate both CSB protein and a conserved CSB-PGBD3 fusion protein in which the first 5 exons of CSB are alternatively spliced to the PGBD3 transposase. Using a host cell reactivation assay, we show that the fusion protein inhibits TCR of oxidative damage but facilitates TCR of UV damage. We also show by microarray analysis that expression of the fusion protein alone in CSB-null UV-sensitive syndrome (UVSS) cells induces an interferon-like response that resembles both the innate antiviral response and the prolonged interferon response normally maintained by unphosphorylated STAT1 (U-STAT1); moreover, as might be expected based on conservation of the fusion protein, this potentially cytotoxic interferon-like response is largely reversed by coexpression of functional CSB protein. Interestingly, expression of CSB and the CSB-PGBD3 fusion protein together, but neither alone, upregulates the insulin growth factor binding protein IGFBP5 and downregulates IGFBP7, suggesting that the fusion protein may also confer a metabolic advantage, perhaps in the presence of DNA damage. Finally, we show that the fusion protein binds in vitro to members of a dispersed family of 900 internally deleted piggyBac elements known as MER85s, providing a potential mechanism by which the fusion protein could exert widespread effects on gene expression. Our data suggest that the CSB-PGBD3 fusion protein is important in both health and disease, and could play a role in Cockayne syndrome.

Publication types

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

MeSH terms

  • Cell Line
  • Cockayne Syndrome / genetics
  • Cockayne Syndrome / metabolism
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / metabolism
  • DNA Helicases / genetics*
  • DNA Helicases / metabolism
  • DNA Repair Enzymes / genetics*
  • DNA Repair Enzymes / metabolism
  • DNA Repair* / radiation effects
  • DNA Transposable Elements*
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Order
  • Humans
  • Immunity, Innate*
  • Interferon-Induced Helicase, IFIH1
  • Interferon-Stimulated Gene Factor 3 / metabolism
  • Interferons / immunology
  • Interferons / metabolism*
  • Mutant Chimeric Proteins / metabolism*
  • Poly-ADP-Ribose Binding Proteins
  • Receptors, Immunologic
  • STAT1 Transcription Factor / metabolism
  • Ultraviolet Rays / adverse effects


  • DNA Transposable Elements
  • Interferon-Stimulated Gene Factor 3
  • Mutant Chimeric Proteins
  • Poly-ADP-Ribose Binding Proteins
  • Receptors, Immunologic
  • STAT1 Transcription Factor
  • Interferons
  • CSB-PGBD3 fusion protein, human
  • DDX58 protein, human
  • IFIH1 protein, human
  • DNA Helicases
  • ERCC6 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases
  • Interferon-Induced Helicase, IFIH1
  • DNA Repair Enzymes