HMG-domain proteins specifically inhibit the repair of the major DNA adduct of the anticancer drug cisplatin by human excision nuclease

Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10394-8. doi: 10.1073/pnas.91.22.10394.

Abstract

The most frequent DNA adduct made by the anticancer drug cisplatin, the 1,2-intrastrand d(GpG) cross-link, as well as the minor 1,3-intrastrand d(GpTpG) adduct, were both repaired by an in vitro human excision repair system. Fragments of 27-29 nt containing the platinum damage were excised. The high mobility group (HMG)-domain proteins HMG1 and human mitochondrial transcription factor specifically inhibited repair of the 1,2-intrastrand cross-link by the human excision nuclease. These results suggest that the types and levels of HMG-domain proteins in a given tumor may influence the responsiveness of that cancer to cisplatin chemotherapy and they provide a rational basis for the synthesis of new platinum anticancer drug candidates.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • Cisplatin / metabolism*
  • DNA Adducts / metabolism*
  • DNA Damage
  • DNA Repair*
  • Endodeoxyribonucleases / metabolism*
  • HeLa Cells
  • High Mobility Group Proteins / metabolism*
  • Humans
  • Kinetics
  • Molecular Sequence Data
  • Oligodeoxyribonucleotides
  • Substrate Specificity

Substances

  • DNA Adducts
  • High Mobility Group Proteins
  • Oligodeoxyribonucleotides
  • cisplatin-DNA adduct
  • Endodeoxyribonucleases
  • Cisplatin