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

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

Affiliations

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

M Masutani et al. Mol Cell Biochem. 1999 Mar.

Abstract

To elucidate the biological functions of poly(ADP-ribose) polymerase (PARP, [EC 2.4.2.30]) 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.

PubMed Disclaimer

References

    1. Prog Nucleic Acid Res Mol Biol. 1973;13:127-51 - PubMed
    1. J Biol Chem. 1995 May 12;270(19):11176-80 - PubMed
    1. Genes Dev. 1995 Mar 1;9(5):509-20 - PubMed
    1. Carcinogenesis. 1985 May;6(5):711-4 - PubMed
    1. Biochem Biophys Res Commun. 1996 Jul 5;224(1):96-102 - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources