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True XP group E patients have a defective UV-damaged DNA binding protein complex and mutations in DDB2 which reveal the functional domains of its p48 product.

Xeroderma pigmentosum (XP) is a skin cancer-prone autosomal recessive disease characterized by inability to repair UV-induced DNA damage. The major form of XP is defective in nucleotide excision repair (NER) and comprises seven complementation groups (A-G). The genes defective in all groups have been identified unambiguously with the exception of group E. The cells of some XP-E patients are deficient in a protein complex (consisting of two subunits: p127/DDBI and p48/DDB2) which binds to UV-damaged DNA (UV-DDB) and is specifically involved in the removal of photoproducts from the non-transcribed regions of the genome. However, other XP-E patients have been reported not to lack UV-damaged DNA binding activity (DDB(+)). Here we describe several genetically unrelated XP-E patients, not previously analyzed in depth, each carrying two mutated alleles for DDB2, causing either a single amino acid change or a protein truncation or internal deletion. These defects result in a severe decrease of detectable p48 protein, abolish interaction with the p127 subunit, and produce a deficiency in UV-DDB binding activity (DDB(-)). The role of p48 in the repair defect of these patients was demonstrated in vivo and in vitro. Investigation of four DDB(+) cell strains from patients previously assigned to XP-E, allowed us to reclassify all of them into other groups and to show that they do not share the molecular and biochemical features typical for XP-E. Besides confirming that the true XP-E phenotype is DDB(-), resulting from defects in a single gene, DDB2, our results identify the functional domains of the corresponding p48 protein.

Pubmed ID: 12812979


  • Rapić-Otrin V
  • Navazza V
  • Nardo T
  • Botta E
  • McLenigan M
  • Bisi DC
  • Levine AS
  • Stefanini M


Human molecular genetics

Publication Data

July 1, 2003

Associated Grants


Mesh Terms

  • Adult
  • Alleles
  • Cell Nucleus
  • Cells, Cultured
  • DNA Mutational Analysis
  • DNA Repair
  • DNA-Binding Proteins
  • Dose-Response Relationship, Radiation
  • Exons
  • Female
  • Gene Deletion
  • Genome
  • Genotype
  • Humans
  • Immunoblotting
  • Male
  • Models, Genetic
  • Mutation
  • Phenotype
  • Precipitin Tests
  • Protein Binding
  • Protein Structure, Tertiary
  • Sequence Analysis, DNA
  • Ultraviolet Rays
  • Xeroderma Pigmentosum