Replication of a cis-syn thymine dimer at atomic resolution

Nature. 2003 Aug 28;424(6952):1083-7. doi: 10.1038/nature01919. Epub 2003 Aug 6.


Ultraviolet light damages DNA by catalysing covalent bond formation between adjacent pyrimidines, generating cis-syn cyclobutane pyrimidine dimers (CPDs) as the most common lesion. CPDs block DNA replication by high-fidelity DNA polymerases, but they can be efficiently bypassed by the Y-family DNA polymerase pol eta. Mutations in POLH encoding pol eta are implicated in nearly 20% of xeroderma pigmentosum, a human disease characterized by extreme sensitivity to sunlight and predisposition to skin cancer. Here we have determined two crystal structures of Dpo4, an archaeal pol eta homologue, complexed with CPD-containing DNA, where the 3' and 5' thymine of the CPD separately serves as a templating base. The 3' thymine of the CPD forms a Watson-Crick base pair with the incoming dideoxyATP, but the 5' thymine forms a Hoogsteen base pair with the dideoxyATP in syn conformation. Dpo4 retains a similar tertiary structure, but each unusual DNA structure is individually fitted into the active site for catalysis. A model of the pol eta-CPD complex built from the crystal structures of Saccharomyces cerevisiae apo-pol eta and the Dpo4-CPD complex suggests unique features that allow pol eta to efficiently bypass CPDs.

MeSH terms

  • Amino Acid Sequence
  • Archaeal Proteins / chemistry
  • Archaeal Proteins / metabolism
  • Base Pairing
  • Base Sequence
  • Binding Sites
  • Crystallization
  • DNA Damage
  • DNA Replication*
  • DNA-Directed DNA Polymerase / chemistry*
  • DNA-Directed DNA Polymerase / metabolism*
  • Models, Molecular
  • Molecular Sequence Data
  • Pyrimidine Dimers / biosynthesis*
  • Pyrimidine Dimers / chemistry*
  • Saccharomyces cerevisiae / enzymology
  • Solutions
  • Structure-Activity Relationship
  • Sulfolobus / enzymology*
  • Templates, Genetic


  • Archaeal Proteins
  • Pyrimidine Dimers
  • Solutions
  • DNA-Directed DNA Polymerase
  • Rad30 protein

Associated data

  • PDB/1PM0
  • PDB/1PM8