Function of poly(ADP-ribose) polymerase in response to DNA damage: gene-disruption study in mice

Mol Cell Biochem. 1999 Mar;193(1-2):149-52.


To elucidate the biological functions of poly(ADP-ribose) polymerase (PARP, [EC]) in DNA damage responses, genetic and biochemical approaches were undertaken. By disrupting exon 1 of the mouse PARP gene by a homologous recombination, PARP-deficient mouse embryonic stem (ES) cell lines and mice could be produced without demonstrating lethality. PARP-/- ES cells showed complete loss of PARP activity and increased sensitivity to gamma-irradiation and an alkylating agents, indicating a physiological role for PARP in the response to DNA damage. p53, a key molecule in cellular DNA damage response, was found to stimulate PARP activity and became poly(ADP-ribosyl)ated in the presence of damaged DNA. However, PARP-/- ES cells showed p21 and Mdm-2 mRNA induction following gamma-irradiation, indicating that PARP activity is not indispensable for p21 and Mdm-2 mRNA induction in the established p53-cascade. On the other hand, in a reconstituted reaction system, purified PARP from human placenta suppressed the pRB-phosphorylation activity in the presence of NAD and damaged DNA. Human PARP expressed in E. coli showed a similar effect on pRB-phosphorylation activity of cdk2. These findings suggest a direct involvement of PARP in the regulation of cdk activity for cell-cycle arrest.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclin-Dependent Kinases / metabolism
  • DNA Damage*
  • Dose-Response Relationship, Drug
  • Dose-Response Relationship, Radiation
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Biological
  • Mutagenesis, Insertional
  • Placenta / metabolism
  • Poly(ADP-ribose) Polymerases / physiology*
  • Tumor Suppressor Protein p53 / metabolism


  • Tumor Suppressor Protein p53
  • Poly(ADP-ribose) Polymerases
  • Cyclin-Dependent Kinases