Structural basis of human DNA polymerase η-mediated chemoresistance to cisplatin

Proc Natl Acad Sci U S A. 2012 May 8;109(19):7269-74. doi: 10.1073/pnas.1202681109. Epub 2012 Apr 23.


Cisplatin (cis-diamminedichloroplatinum) and related compounds cause DNA damage and are widely used as anticancer agents. Chemoresistance to cisplatin treatment is due in part to translesion synthesis by human DNA polymerase η (hPol η). Here, we report crystal structures of hPol η complexed with intrastrand cisplatin-1,2-cross-linked DNA, representing four consecutive steps in translesion synthesis. In contrast to the generally enlarged and nondiscriminating active site of Y-family polymerases like Dpo4, Pol η is specialized for efficient bypass of UV-cross-linked pyrimidine dimers. Human Pol η differs from the yeast homolog in its binding of DNA template. To incorporate deoxycytidine opposite cisplatin-cross-linked guanines, hPol η undergoes a specific backbone rearrangement to accommodate the larger base dimer and minimizes the DNA distortion around the lesion. Our structural analyses show why Pol η is inefficient at extending primers after cisplatin lesions, which necessitates a second translesion DNA polymerase to complete bypass in vivo. A hydrophobic pocket near the primer-binding site in human Pol η is identified as a potential drug target for inhibiting translesion synthesis and, thereby, reducing chemoresistance.

Publication types

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

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism
  • Base Sequence
  • Binding Sites / genetics
  • Cisplatin / chemistry*
  • Cisplatin / pharmacology
  • Cross-Linking Reagents / chemistry
  • Cross-Linking Reagents / pharmacology
  • Crystallography, X-Ray
  • DNA / chemistry*
  • DNA / genetics
  • DNA / metabolism
  • DNA-Directed DNA Polymerase / chemistry*
  • DNA-Directed DNA Polymerase / genetics
  • DNA-Directed DNA Polymerase / metabolism
  • Drug Resistance*
  • Humans
  • Kinetics
  • Models, Molecular
  • Molecular Structure
  • Mutation
  • Neoplasms / drug therapy
  • Neoplasms / enzymology
  • Neoplasms / genetics
  • Nucleic Acid Conformation
  • Protein Conformation
  • Protein Structure, Tertiary
  • Pyrimidine Dimers / chemistry
  • Pyrimidine Dimers / metabolism
  • Sequence Homology, Amino Acid


  • Cross-Linking Reagents
  • Pyrimidine Dimers
  • Adenosine Triphosphate
  • DNA
  • DNA-Directed DNA Polymerase
  • Rad30 protein
  • Cisplatin

Associated data

  • PDB/4DL2
  • PDB/4DL3
  • PDB/4DL4
  • PDB/4DL5
  • PDB/4DL6
  • PDB/4DL7