Home LiteratureArticle Details
PMID: 10331651 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Molecular and cellular biochemistry ·Vol. 193 ·No. 1-2 ·1999-03-00 ·Pages 149-52

Masutani M, Nozaki T, Nishiyama E, Shimokawa T, Tachi Y, Suzuki H, Nakagama H, Wakabayashi K, Sugimura T

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.

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
Chemicals
Tumor Suppressor Protein p53 Poly(ADP-ribose) Polymerases Cyclin-Dependent Kinases
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Masutani M
Biochemistry Division, National Cancer Center Research Institute, Tokyo, Japan.
Nozaki T
Nishiyama E
Shimokawa T
Tachi Y
Suzuki H
Nakagama H
Wakabayashi K
Sugimura T
References (16)
16 references, click to expand
  1. Poly(adenosine diphosphate ribose).
    Prog Nucleic Acid Res Mol Biol. 1973;13:127-51 PMID: 4349570
  2. Inactivation of the poly(ADP-ribose) polymerase gene affects oxygen radical and nitric oxide toxicity in islet cells.
    J Biol Chem. 1995 May 12;270(19):11176-80 PMID: 7744749
  3. Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease.
    Genes Dev. 1995 Mar 1;9(5):509-20 PMID: 7698643
  4. Cell cycle perturbations following DNA damage in the presence of ADP-ribosylation inhibitors.
    Carcinogenesis. 1985 May;6(5):711-4 PMID: 2988807
  5. ADP-ribosylation of wild-type p53 in vitro: binding of p53 protein to specific p53 consensus sequence prevents its modification.
    Biochem Biophys Res Commun. 1996 Jul 5;224(1):96-102 PMID: 8694840
  6. Suppression of G1 arrest and enhancement of G2 arrest by inhibitors of poly(ADP-ribose) polymerase: possible involvement of poly(ADP-ribosyl)ation in cell cycle arrest following gamma-irradiation.
    Jpn J Cancer Res. 1994 Nov;85(11):1094-8 PMID: 7829393
  7. Role of poly(ADP-ribose) polymerase in cell-cycle checkpoint mechanisms following gamma-irradiation.
    Biochimie. 1995;77(6):462-5 PMID: 7578430
  8. Defects in a cell cycle checkpoint may be responsible for the genomic instability of cancer cells.
    Cell. 1992 Nov 13;71(4):543-6 PMID: 1423612
  9. A dominant-negative mutant of human poly(ADP-ribose) polymerase affects cell recovery, apoptosis, and sister chromatid exchange following DNA damage.
    Proc Natl Acad Sci U S A. 1995 May 23;92(11):4753-7 PMID: 7761396
  10. Stable production of mutant mice from double gene converted ES cells with puromycin and neomycin.
    Biochem Biophys Res Commun. 1995 Aug 4;213(1):130-7 PMID: 7639726
  11. Role of poly(ADP-ribose) formation in DNA repair.
    Nature. 1992 Mar 26;356(6367):356-8 PMID: 1549180
  12. Participation of p53 protein in the cellular response to DNA damage.
    Cancer Res. 1991 Dec 1;51(23 Pt 1):6304-11 PMID: 1933891
  13. (ADP-ribose)n participates in DNA excision repair.
    Nature. 1980 Feb 7;283(5747):593-6 PMID: 6243744
  14. Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE.
    Nature. 1994 Sep 22;371(6495):346-7 PMID: 8090205
  15. Depletion of poly(ADP-ribose) polymerase by antisense RNA expression results in a delay in DNA strand break rejoining.
    J Biol Chem. 1992 Jun 25;267(18):12804-12 PMID: 1618781
  16. Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells.
    Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7303-7 PMID: 9207086
Article Info
Journal
Molecular and cellular biochemistry
Abbr.
Mol Cell Biochem
ISSN
0300-8177
Published
1999-03-00
Pages
149-52
Language
English
Region
Netherlands
NLM ID
0364456
Subset
IM
External Links
PubMed source View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2