Repair of and checkpoint response to topoisomerase I-mediated DNA damage

Mutat Res. 2003 Nov 27;532(1-2):173-203. doi: 10.1016/j.mrfmmm.2003.08.016.


Topoisomerase I (Top1) catalyzes two transesterification reactions: single-strand DNA cleavage and religation that are normally coupled for the relaxation of DNA supercoiling in transcribing and replicating chromatin. A variety of endogenous DNA modifications, potent anticancer drugs and carcinogens uncouple these two reactions, resulting in the accumulation of Top1 cleavage complexes. Top1 cleavage complexes damage DNA and kill cells by generating replication-mediated DNA double-strand breaks (DSBs) and by stalling transcription complexes. The repair of Top1-mediated DNA lesions involves integrated pathways that are conserved from yeasts to humans. Top1-mediated DNA damage and cell cycle checkpoint responses can be studied biochemically and genetically in yeast and human cells with known genetic defects. Defects in these repair/checkpoint pathways, which promote tumor development, explain, at least in part, the selectivity of camptothecins and other Top1 inhibitors for cancer cells.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Cycle*
  • DNA / metabolism
  • DNA Damage*
  • DNA Repair
  • DNA Topoisomerases, Type I / physiology*
  • Humans
  • Models, Biological
  • Protein Binding
  • Recombination, Genetic / drug effects


  • Antineoplastic Agents
  • DNA
  • DNA Topoisomerases, Type I