Mutations in UVSSA cause UV-sensitive syndrome and destabilize ERCC6 in transcription-coupled DNA repair

Nat Genet. 2012 May;44(5):593-7. doi: 10.1038/ng.2228.

Abstract

UV-sensitive syndrome (UV(S)S) is an autosomal recessive disorder characterized by photosensitivity and deficiency in transcription-coupled repair (TCR), a subpathway of nucleotide-excision repair that rapidly removes transcription-blocking DNA damage. Cockayne syndrome is a related disorder with defective TCR and consists of two complementation groups, Cockayne syndrome (CS)-A and CS-B, which are caused by mutations in ERCC8 (CSA) and ERCC6 (CSB), respectively. UV(S)S comprises three groups, UV(S)S/CS-A, UV(S)S/CS-B and UV(S)S-A, caused by mutations in ERCC8, ERCC6 and an unidentified gene, respectively. Here, we report the cloning of the gene mutated in UV(S)S-A by microcell-mediated chromosome transfer. The predicted human gene UVSSA (formerly known as KIAA1530)(7) corrects defective TCR in UV(S)S-A cells. We identify three nonsense and frameshift UVSSA mutations in individuals with UV(S)S-A, indicating that UVSSA is the causative gene for this syndrome. The UVSSA protein forms a complex with USP7 (ref. 8), stabilizes ERCC6 and restores the hypophosphorylated form of RNA polymerase II after UV irradiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / genetics*
  • Cells, Cultured
  • Cockayne Syndrome / genetics*
  • DNA Damage / genetics
  • DNA Damage / radiation effects
  • DNA Helicases / chemistry*
  • DNA Helicases / genetics
  • DNA Repair / genetics*
  • DNA Repair / radiation effects
  • DNA Repair Enzymes / chemistry*
  • DNA Repair Enzymes / genetics
  • Exome / genetics
  • Humans
  • Kidney / cytology
  • Kidney / metabolism
  • Mutation / genetics*
  • Poly-ADP-Ribose Binding Proteins
  • Protein Stability / radiation effects*
  • RNA Polymerase II / metabolism
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription, Genetic*
  • Ultraviolet Rays*

Substances

  • Carrier Proteins
  • ERCC8 protein, human
  • Poly-ADP-Ribose Binding Proteins
  • Transcription Factors
  • UVSSA protein, human
  • RNA Polymerase II
  • DNA Helicases
  • ERCC6 protein, human
  • DNA Repair Enzymes