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Poly(ADP-RIBOSE) polymerase-1 (Parp-1) antagonizes topoisomerase I-dependent recombination stimulation by P53

Cindy Baumann1, Gisa S Boehden, Alexander Bürkle

  • 1Universitätsfrauenklinik, Prittwitzstrasse 43 D-89075 Ulm, Germany.

Nucleic Acids Research
|February 14, 2006
PubMed

Insights

Poly(ADP-ribose) polymerase 1 (PARP-1) counteracts p53

Area of Science:

  • Molecular Biology
  • DNA Repair Mechanisms
  • Cancer Research

Background:

  • PARP-1 interacts with p53 and topoisomerase I, key players in DNA recombination.
  • PARP-1 is known to downregulate homology-directed double-strand break (DSB) repair.
  • p53, typically a suppressor of error-prone recombination, enhances homologous recombination (HR) at specific sites involving topoisomerase I.

Purpose of the Study:

  • To investigate the interplay between PARP-1 and p53 in regulating homologous recombination (HR).
  • To elucidate the role of topoisomerase I in the regulatory mechanism.
  • To determine whether PARP-1's effect is mediated by poly(ADP-ribosyl)ation or direct interaction.

Main Methods:

  • Utilized an SV40-based assay and isogenic cell lines with varying p53 and PARP-1 status.
  • Employed episomal recombination plasmids and chromosomally integrated DNA substrates.
  • Performed siRNA-mediated knockdown of topoisomerase I and utilized I-SceI-meganuclease cleavage.

Main Results:

  • PARP-1 antagonizes p53-mediated HR enhancement in chromosomally integrated substrates.
  • Both p53 and PARP-1 showed anti-recombinogenic activity on episomal plasmids.
  • Topoisomerase I is essential for the regulatory mechanism, but its role is not observed after specific cleavage.
  • PARP-1 likely prevents p53 from stimulating HR via topoisomerase I interaction, not poly(ADP-ribosyl)ation.

Conclusions:

  • PARP-1 negatively regulates p53-stimulated homologous recombination on chromosomes.
  • The interaction between PARP-1 and topoisomerase I is crucial for this regulation.
  • PARP-1's inhibitory effect on p53-mediated HR is likely independent of its poly(ADP-ribosyl)ation activity.

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