Poly(ADP-ribose) Polymerase-1 Is a Positive Regulator of the p53-mediated G1 Arrest Response following Ionizing Radiation

Poly(ADP-ribose) polymerase-1 (PARP-1) and the p53 tumor suppressor protein are both involved in the cellular response to genotoxic stress. Upon binding to the site of DNA strand breakage, PARP-1 is activated, leading to rapid and transient poly(ADP-ribosyl)ation of nuclear proteins using NAD+ as substrate. To investigate the role of PARP-1 in the p53 response to ionizing radiation in human cells, PARP-1 function was disrupted in wild-type p53 expressing MCF-7 and BJ/TERT cells using two strategies: chemical inhibition with 1,5-dihydroxyisoquinoline, and trans-dominant inhibition by overexpression of the PARP-1 DNA-binding domain. Although a number of proteins can catalyze poly(ADP-ribosyl)ation in addition to PARP-1, we show that PARP-1 is the only detectable active species in BJ/TERT and MCF-7 cells. 1,5-Dihydroxyisoquinoline treatment prior to ionizing radiation delayed and attenuated the induction of two p53-responsive genes, p21 and mdm-2, and led to suppression of the p53-mediated G1-arrest response in MCF-7 and BJ/TERT cells. Trans-dominant inhibition of PARP-1 by overexpression of the PARP-1 DNA-binding domain in MCF-7 cells also led to a delay and attenuation in p21 induction and suppression of the p53-mediated G1 arrest response to ionizing radiation. Hence, inhibition of endogenous PARP-1 function suppresses the transactivation function of p53 in response to ionizing radiation. This study establishes PARP-1 as a critical regulator of the p53 response to DNA damage. Poly(ADP-ribose) polymerase-1 (PARP-1) and the p53 tumor suppressor protein are both involved in the cellular response to genotoxic stress. Upon binding to the site of DNA strand breakage, PARP-1 is activated, leading to rapid and transient poly(ADP-ribosyl)ation of nuclear proteins using NAD+ as substrate. To investigate the role of PARP-1 in the p53 response to ionizing radiation in human cells, PARP-1 function was disrupted in wild-type p53 expressing MCF-7 and BJ/TERT cells using two strategies: chemical inhibition with 1,5-dihydroxyisoquinoline, and trans-dominant inhibition by overexpression of the PARP-1 DNA-binding domain. Although a number of proteins can catalyze poly(ADP-ribosyl)ation in addition to PARP-1, we show that PARP-1 is the only detectable active species in BJ/TERT and MCF-7 cells. 1,5-Dihydroxyisoquinoline treatment prior to ionizing radiation delayed and attenuated the induction of two p53-responsive genes, p21 and mdm-2, and led to suppression of the p53-mediated G1-arrest response in MCF-7 and BJ/TERT cells. Trans-dominant inhibition of PARP-1 by overexpression of the PARP-1 DNA-binding domain in MCF-7 cells also led to a delay and attenuation in p21 induction and suppression of the p53-mediated G1 arrest response to ionizing radiation. Hence, inhibition of endogenous PARP-1 function suppresses the transactivation function of p53 in response to ionizing radiation. This study establishes PARP-1 as a critical regulator of the p53 response to DNA damage. The p53 tumor suppressor protein plays a critical role in the cellular response to DNA damage leading to cell cycle arrest or apoptosis depending on cell type, culture conditions, and the extent of DNA damage. Loss of the p53-dependent DNA damage response can lead to genomic instability and the survival of cells carrying mutations and carcinogenic lesions thereby contributing to malignancy (1Levine A.J. Cell. 1997; 88: 323-331Abstract Full Text Full Text PDF PubMed Scopus (6804) Google Scholar). DNA strand breaks produced by ionizing radiation (IR) 1The abbreviations used are: IR, ionizing radiation; PARP, poly(ADP-ribose) polymerase; pADPr, poly(ADP-ribose); IQ, 1,5-dihydroxyisoquinoline; DBD, DNA-binding domain; PBS, phosphate-buffered saline; Me2SO, dimethyl sulfoxide; GFP, green fluorescent protein; PI, propidium iodide; Gy, gray; GAPDH, glyceraldehyde-3-phosphate dehydrogenase. or by DNA repair intermediates following treatment with UV radiation or chemotherapeutic agents result in the accumulation of p53 protein and in the activation of its transcriptional activity (reviewed in Refs. 2Giaccia A.J. Kastan M.B. Genes Dev. 1998; 12: 2973-2983Crossref PubMed Scopus (1184) Google Scholar and 3Prives C. Hall P.A. J. Pathol. 1999; 187: 112-126Crossref PubMed Scopus (1243) Google Scholar). Elevated levels of p53 protein are believed to be important to initiate the events that lead to G1 arrest or apoptosis after DNA damage. There is compelling evidence that post-translational modification of p53 is required for its stabilization, as well as for activation of its latent sequence-specific DNA-binding and transactivation functions. Once p53 becomes activated it binds as a tetramer to p53 responsive elements on double stranded DNA consisting of two half-sites (5′-PuPuPuC(A/T)(T/A)GPyPyPy-3′) separated by a spacer consisting of 0–13 nucleotides (4el-Deiry W.S. Kern S.E. Pietenpol J.A. Kinzler K.W. Vogelstein B. Nat. Genet. 1992; 1: 45-49Crossref PubMed Scopus (1780) Google Scholar). The site-specific DNA-binding activity of p53 leads to transcriptional activation of p53 target genes. Covalent modification of p53 has also been shown to regulate its subcellular localization, tetramerization, interaction with other proteins, and degradation. p53 protein is modified in vivo through phosphorylation, acetylation, poly(ADP-ribosyl)ation, ubiquitination, and sumoylation reactions (reviewed in Refs. 2Giaccia A.J. Kastan M.B. Genes Dev. 1998; 12: 2973-2983Crossref PubMed Scopus (1184) Google Scholar and 5Jayaraman L. Prives C. Cell Mol. Life Sci. 1999; 55: 76-87Crossref PubMed Scopus (124) Google Scholar). The events upstream of p53 activation are complex and not well understood. Several DNA damage sensory molecules are believed to relay the DNA damage signal to p53; each may be involved in the response to one or more types of DNA damage. For example, ataxia-telangiectasia-mutated kinase protein is involved in the activation of p53 in response to IR (6Canman C.E. Lim D.S. Cimprich K.A. Taya Y. Tamai K. Sakaguchi K. Appella E. Kastan M.B. Siliciano J.D. Science. 1998; 281: 1677-1679Crossref PubMed Scopus (1722) Google Scholar, 7Banin S. Moyal L. Shieh S. Taya Y. Anderson C.W. Chessa L. Smorodinsky N.I. Prives C. Reiss Y. Shiloh Y. Ziv Y. Science. 1998; 281: 1674-1677Crossref PubMed Scopus (1722) Google Scholar), and ataxia telangiectasia-related kinase protein is involved in the activation of p53 in response to UV irradiation (8Tibbetts R.S. Brumbaugh K.M. Williams J.M. Sarkaria J.N. Cliby W.A. Shieh S.Y. Taya Y. Prives C. Abraham R.T. Genes Dev. 1999; 13: 152-157Crossref PubMed Scopus (876) Google Scholar). Poly(ADP-ribose) polymerase (PARP-1) is an abundant nuclear enzyme that binds to, and is activated by, DNA single and double strand breaks (reviewed in Refs. 9D'Amours D. Desnoyers S. D'Silva I. Poirier G.G. Biochem. J. 1999; 342: 249-268Crossref PubMed Scopus (0) Google Scholar, 10Shall S. de Murcia G. Mutat. Res. 2000; 460: 1-15Crossref PubMed Scopus (480) Google Scholar, 11Herceg Z. Wang Z.Q. Mutat. Res. 2001; 477: 97-110Crossref PubMed Scopus (424) Google Scholar). Its activation represents one of the earliest responses to DNA damage in the cell. PARP-1 catalyzes the sequential transfer of ADP-ribose monomers onto nuclear protein acceptors using NAD+ as substrate. During the process of poly(ADP-ribosyl)ation, NAD+ is hydrolyzed and released as free nicotinamide. More than 30 nuclear proteins have been identified as poly(ADP-ribose) (pADPr) acceptors, with PARP-1 itself being the major target, via its automodification domain. pADPr acceptor proteins may be modified through covalent as well as through non-covalent association with pADPr, either free or bound to PARP-1. Poly(ADP-ribose) glycohydrolase is the major enzyme responsible for the hydrolysis of pADPr. There is general agreement, based on genetic and biochemical studies, that PARP-1 plays a critical role in the maintenance of genomic integrity. PARP-1 and p53 have been shown to interact in a number of cell lines including the human leukemia-derived cell line OCI/AML-3 (12Vaziri H. West M.D. Allsopp R.C. Davison T.S. Wu Y.S. Arrowsmith C.H. Poirier G.G. Benchimol S. EMBO J. 1997; 16: 6018-6033Crossref PubMed Scopus (336) Google Scholar). The oligomerization and DNA-binding domains of p53 contain copies of the recently characterized pADPr-binding site (13Pleschke J.M. Kleczkowska H.E. Strohm M. Althaus F.R. J. Biol. Chem. 2000; 275: 40974-40980Abstract Full Text Full Text PDF PubMed Scopus (464) Google Scholar). Furthermore, pADPr has been shown to interact non-covalently with p53 in vitro (14Malanga M. Pleschke J.M. Kleczkowska H.E. Althaus F.R. J. Biol. Chem. 1998; 273: 11839-11843Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar), and p53 can be covalently poly(ADP-ribosyl)ated in vitro J. G. C. Biochem. Res. PubMed Scopus Google Scholar, H. Res. 1998; Google and in cells apoptosis D.S. Res. 1999; Google Scholar). show that poly(ADP-ribosyl)ation of p53 can with its site-specific DNA-binding activity H. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, D.S. M. 2001; PubMed Scopus Google Scholar). The of PARP-1 to interact with and p53 a two is that PARP-1 as a DNA damage that p53 function in response to DNA damage. number of have the role of PARP-1 in the p53 response to DNA damage. Several that of function by chemical inhibition leads to suppression of p53-dependent transactivation in response to IR (12Vaziri H. West M.D. Allsopp R.C. Davison T.S. Wu Y.S. Arrowsmith C.H. Poirier G.G. Benchimol S. EMBO J. 1997; 16: 6018-6033Crossref PubMed Scopus (336) Google Scholar, M. K. PubMed Scopus Google Scholar, K. 1998; PubMed Scopus Google Scholar). inhibition of leads to of the G1 and accumulation of cells in following treatment J. PubMed Scopus Google or IR M. K. PubMed Scopus Google Scholar). PARP-1 C. B. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar), and PARP-1 Murcia J.M. C. C. M. B. M. M. M. C. de Murcia G. Sci. S. 1997; PubMed Scopus Google Scholar, Wang Z.Q. 1997; PubMed Scopus Google Scholar, J. Wang Z.Q. G. Res. 1999; Google Scholar, M. E. Y. H. H. K. Mol. Cell. Biochem. 1999; PubMed Google have and using cells are by the that cells poly(ADP-ribosyl)ation activity Wang Z.Q. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, F.R. M.D. Wang Z.Q. Poirier G.G. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). PARP-1 plays a role in the maintenance of genomic the PARP-1 and p53 we have disrupted PARP-1 function in human cells using two strategies: chemical inhibition with the and trans-dominant inhibition by overexpression of the DNA-binding domain of PARP-1. have the of PARP-1 on p53-dependent DNA damage response in MCF-7 human cells and in BJ/TERT cells human that have been by of the enzyme H. Benchimol S. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). that inhibition of PARP-1 activity with or with PARP-1 overexpression suppresses the transactivation function of p53 and the of p53 to G1 arrest in response to ionizing radiation. This the that PARP-1 is a critical regulator of p53 function in response to DNA damage. Cell and and cells in with in a To cells, a the domain of p53 was the site of The was with cells and the used to BJ/TERT cells. The cells and shown to a p53-dependent G1 in response to ionizing radiation. cells the with wild-type p53 protein to E. D. M. Mol. Cell. Biol. 1992; 12: PubMed Scopus Google Scholar). are MCF-7 cells that the D. M. Cell. Full Text PDF PubMed Scopus Google Scholar). cells, the p53 is and wild-type For inhibition of activity was to the cells prior to The by and for MCF-7 and BJ/TERT cells, not cells with phosphate-buffered and and with was in dimethyl that the of to cells not in a a of a of was for the MCF-7 we to a of for with MCF-7 and BJ/TERT cells. are to the p53-mediated DNA damage the extent of cell is following than in cell lines H. J.A. G. H. S. Benchimol S. Mol. Cell. Biol. 1999; PubMed Scopus Google Scholar, J. Biol. 1997; PubMed Scopus Google for a for by in PBS, and in or and in the in with the using a For the MCF-7 MCF-7 cells with of that the PARP-1 de Murcia G. J. Biol. Chem. Full Text PDF PubMed Google or the cells. To the cells with of a green fluorescent protein For the MCF-7 cell cycle cells with of a the and of or the of and to and with with was and the cells to and the The nuclear was with The nuclear and in and and for by on a in The proteins onto a of the proteins in the in the with DNA and To non-covalently bound pADPr, the in was in the bound pADPr was by with PBS, with either or with and for For the BJ/TERT and protein DNA was by in a of the cell was using a modified addition of and the protein for by on an and by onto p53 for for BJ/TERT and p21 and PARP-1 used in with or and the using the Life For the BJ/TERT and was used to of was BJ/TERT and MCF-7 cells using a modified to the was by of each was separated on a and to The was with to p21 and was and using Cell the G1 arrest response in MCF-7 and BJ/TERT cells, cells on culture cells, BJ/TERT cells with BJ/TERT and Cell cycle was by using the propidium DNA BJ/TERT and cells with and on in and to and for DNA by For the BJ/TERT cells with and with for and by one in PBS, cells with in and in the in and for 30 cells for DNA by MCF-7 and cells for as for the BJ/TERT For of transient overexpression of the PARP-1 DBD, MCF-7 cells as cells on culture and and for with the following cells with a for 30 prior to and was and cells for DNA Cell cycle was with a using The of cells in each of the cell cycle was using MCF-7 and BJ/TERT a with and to that cells two proteins with activity to activity in human MCF-7 and BJ/TERT cells using an in based activity with nuclear and to BJ/TERT and MCF-7 cells. PARP-1 was as a has been shown that have two active a major active to the PARP-1 and a active with an of to F.R. M.D. Wang Z.Q. Poirier G.G. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). the human cell lines BJ/TERT and MCF-7 only one protein species of in the of DNA strand by the DNA This protein is in the nuclear and to PARP-1. of PARP-1 is also in the activity DNA to a that PARP-1 poly(ADP-ribosyl)ation activity is activated by DNA strand of by p21 and following inhibition of activity with as and has been shown to p53-dependent induction of p21 following DNA damage in cell including the human leukemia-derived OCI/AML-3 cell line (12Vaziri H. West M.D. Allsopp R.C. Davison T.S. Wu Y.S. Arrowsmith C.H. Poirier G.G. Benchimol S. EMBO J. 1997; 16: 6018-6033Crossref PubMed Scopus (336) Google Scholar). To investigate the of inhibition on the MCF-7 and BJ/TERT cell cells with BJ/TERT for Gy, BJ/TERT and a the and and IR, cells not with induction of both p21 and mdm-2, as treatment with the chemical in a delay in the of induction of both proteins and to a suppression of and p21 protein was the of p21 accumulation in was by of the with an to or by with and not BJ/TERT and MCF-7 cells with levels of both p53 and p53 protein induction following IR was in both the and BJ/TERT cells the accumulation of p53 was in the of MCF-7 cells with IQ, we not induction of p53 the cells the of This has been shown to as a trans-dominant of p53 through its to the of p53 E. D. M. Mol. Cell. Biol. 1992; 12: PubMed Scopus Google Scholar). p53 levels are in cells the of with the abundant cells to p21 or in response to IR that the induction of p21 and in BJ/TERT cells is on p53 of by of p21 following p53-dependent of p21 protein levels in response to ionizing radiation is the transcriptional to investigate inhibition with with the transactivation function of BJ/TERT and MCF-7 cells with or and with or Gy, was the and was using led p21 and to GAPDH, levels and MCF-7 cells, p21 levels by following IR, and MCF-7 cells with IQ, the induction of p21 following IR was delayed by to with cells, an to that the protein BJ/TERT cells a more prior treatment with led to suppression of p21 induction that suppresses induction of p21 in response to IR by with the transactivation function of of by the p53-mediated following is a critical of the p53-mediated G1 arrest response following DNA damage. MCF-7 cells and BJ/TERT cells G1 arrest in response to of ionizing radiation H. J.A. G. H. S. Benchimol S. Mol. Cell. Biol. 1999; PubMed Scopus Google Scholar, J. Biol. 1997; PubMed Scopus Google Scholar). result that inhibition suppresses p53-mediated transactivation of p21 that inhibition lead to of the p53-dependent G1 To cell cycle using to DNA was BJ/TERT and cells with IQ, Gy, and cell cycle by The of cells in each of the cell cycle was in or and the shown are the addition to G1 ionizing radiation can lead to arrest in and can result in a in the of cells in the G1 and of the cell For it is important to the an in the following DNA damage has been used as an of G1 BJ/TERT cells a in the following IR, that cells G1 cells in the after IR that G1 arrest is on BJ/TERT cells with a in p53-mediated G1 by a BJ/TERT cells with or and of cells was to the cell cycle for both cells and cells with The of cells in each cell cycle and The S.E. are shown for BJ/TERT cells a G1 arrest response by and cells in a treatment of BJ/TERT cells delayed and attenuated G1 arrest inhibition of the cell cycle of BJ/TERT cells following ionizing radiation. BJ/TERT cells with or for and the in and with in DNA was with a and cell cycle using of chemical inhibition of on cell cycle of BJ/TERT cells following of cells in each cell cycle and for the BJ/TERT shown in using The S.E. are shown for in a also the of on the p53-mediated G1 in MCF-7 cells and in MCF-7 cells expressing a p53 with IQ, Gy, and the cell cycle by The was based on that G1 arrest can be in MCF-7 cell to following IR not shown are the MCF-7 cells a in the after IR of G1 in G1 was in cells in the of cells only a in the after IR that G1 arrest in cells is by with a of not that inhibition of activity with suppresses the transactivation function of p53 and the of p53 to G1 arrest in response to of PARP-1 by Trans-dominant p21 following important using chemical is the of may target other in addition to PARP-1. To important we to p53 activity in human cells PARP-1 activity be through The the DNA-binding domain of PARP-1, and has been shown to function as a trans-dominant of PARP-1 through its to for binding to DNA strand breaks de Murcia G. J. Biol. Chem. Full Text PDF PubMed Google Scholar). we BJ/TERT expressing PARP-1 of poly(ADP-ribosyl)ation of nuclear proteins was PARP-1 was not of activity is not the result of as in PARP-1 F.R. M.D. Wang Z.Q. Poirier G.G. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar), PARP-1 is the only enzyme in BJ/TERT cells. it may be the result of in the is also that PARP-1 activity is required for survival of the BJ/TERT cells. a we transient The has been used in transient to function de Murcia G. J. Biol. Chem. Full Text PDF PubMed Google Scholar, M. Murcia J. de Murcia G. EMBO J. 12: PubMed Scopus Google Scholar). The of BJ/TERT is and we to transient of PARP-1 in cells. to MCF-7 cells that have an of with cells Gy, as with the MCF-7 and protein the cell and the and by The PARP-1 was only in cells with and not in cells with the p21 levels and the induction of p21 protein following IR was delayed and attenuated in cells expressing the PARP-1 of PARP-1 by Trans-dominant the p53-mediated following to PARP-1 overexpression the p53-dependent G1 in MCF-7 cells. or with the the cell after after IR, cells identified by and the cell cycle of the and cell by and The cells that not and as in The both the and the G1 arrest following IR by the in the and The cells with a in the following IR This is with the cells and is of arrest in cells with the only a in the a suppression of the G1 DNA damage by ionizing radiation and the nuclear enzyme PARP-1 is activated leading to rapid and transient poly(ADP-ribosyl)ation of nuclear proteins L. S. de Murcia G. Althaus F.R. J. Biol. Chem. Full Text PDF PubMed Google Scholar). of PARP-1 a critical role for PARP-1 in the maintenance of genomic (reviewed in Refs. 10Shall S. de Murcia G. Mutat. Res. 2000; 460: 1-15Crossref PubMed Scopus (480) Google Scholar and 11Herceg Z. Wang Z.Q. Mutat. Res. 2001; 477: 97-110Crossref PubMed Scopus (424) Google the through PARP-1 in the cellular response to genotoxic and in DNA repair are not understood. Several an role for PARP-1 in response to DNA PARP-1 is to strand breaks it may as a of DNA damage to repair Poirier G.G. PubMed Scopus Google Scholar, Poirier G.G. Biochem. Sci. Full Text PDF PubMed Scopus Google Scholar). proteins may also be to DNA strand breaks to in the repair of may to following DNA to to DNA repair F.R. L. Kleczkowska H.E. M. H. C. Scopus Google Scholar). The p53 tumor suppressor also plays a critical role in the cellular response to DNA damage. cells that have been to genotoxic as ionizing UV or p53 of target that are involved in either cell cycle arrest or responses that mutations are not and that genetic is (1Levine A.J. Cell. 1997; 88: 323-331Abstract Full Text Full Text PDF PubMed Scopus (6804) Google Scholar, C.E. Kastan M.B. Genes Dev. PubMed Scopus Google Scholar). have shown that p53 protein can to PARP-1 in the human leukemia-derived OCI/AML-3 cell the we also that of NAD+ that endogenous poly(ADP-ribosyl)ation are to p53-dependent in human (12Vaziri H. West M.D. Allsopp R.C. Davison T.S. Wu Y.S. Arrowsmith C.H. Poirier G.G. Benchimol S. EMBO J. 1997; 16: 6018-6033Crossref PubMed Scopus (336) Google Scholar). have shown that p53 can be poly(ADP-ribosyl)ated in vivo D.S. Res. 1999; Google and in vitro J. G. C. Biochem. Res. PubMed Scopus Google Scholar, H. Res. 1998; Google Scholar, H. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). the we have the PARP-1 and two to PARP-1 we have an attenuation of the activity of the p53 protein as a the p21 in two human cell cell types a p53-dependent arrest in the G1 of the cell cycle following ionizing radiation. that inhibition of PARP-1 activity a of p53-mediated G1 arrest following ionizing radiation. a critical role for PARP-1 in the p53-dependent G1 Although inhibition of PARP-1 by treatment led to on p53 transactivation function in BJ/TERT and MCF-7 cells, it on p53 induction and The induction of p53 protein in BJ/TERT cells was by MCF-7 cells with not show p53 induction the following the of a of that catalyze S. I. de Science. 1998; PubMed Scopus Google Scholar), Y. J. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), and C. M. J. Cell Biol. 1999; PubMed Scopus Google Scholar), that are not activated by DNA strand has been shown to to and be activated by DNA strand protein the DNA-binding domain of PARP-1 C. S. Murcia J. de Murcia G. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). a DNA-binding can be activated by DNA damage F.R. M.D. Wang Z.Q. Poirier G.G. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). we have only been to one species of in BJ/TERT and MCF-7 cells, PARP-1. This the that is upstream of p53 in response to DNA damage. Trans-dominant inhibition of PARP-1 led to a delay in both and MCF-7 cells, that PARP-1 may be involved in was in MCF-7 and BJ/TERT cells with IQ, in with using the chemical M. K. PubMed Scopus Google Scholar, M. H. J. Res. PubMed Scopus Google the delay was more in cells as with the PARP-1 that chemical inhibition by may lead to on the The of treatment on the p53 response to IR in study are with (12Vaziri H. West M.D. Allsopp R.C. Davison T.S. Wu Y.S. Arrowsmith C.H. Poirier G.G. Benchimol S. EMBO J. 1997; 16: 6018-6033Crossref PubMed Scopus (336) Google Scholar, M. K. PubMed Scopus Google Scholar, K. 1998; PubMed Scopus Google Scholar, M. H. J. Res. PubMed Scopus Google the of to activity can be of the of on other for example, that M. J. Cell PubMed Scopus Google Scholar). trans-dominant inhibition of PARP-1 by PARP-1 overexpression led to of p21 induction and suppression of p53-mediated G1 arrest in MCF-7 cells. that chemical inhibition of by the p53-mediated G1 in MCF-7 cells by with PARP-1 an of PARP-1 in transcriptional that PARP-1 can either or activity of PARP-1 the DNA binding not the function of PARP-1 (reviewed in M. 2001; PubMed Scopus Google Scholar). Hence, PARP-1 may in addition to the activity of PARP-1. This the of using to PARP-1 During the of we an of p53 and p21 protein in BJ/TERT and MCF-7 cells, and in MCF-7 cells. p21 levels are not in cells that in is are the of DNA damage a function of the not the of DNA damage response DNA damage lead to binding of the to DNA strand to The through PARP-1 p53 activity to be is covalent poly(ADP-ribosyl)ation of of p53 has been in vivo in cells apoptosis D.S. Res. 1999; Google Scholar, B. S. B. Wang Z.Q. M. D.S. 2000; PubMed Scopus Google Scholar). To has been of poly(ADP-ribosyl)ation of p53 following DNA damage. is that p53 with pADPr, either free or bound to nuclear protein acceptors as PARP-1. the and DNA-binding domains have been to interact with pADPr in vitro (14Malanga M. Pleschke J.M. Kleczkowska H.E. Althaus F.R. J. Biol. Chem. 1998; 273: 11839-11843Abstract Full Text Full Text PDF PubMed Scopus (198) Google contain pADPr-binding as by (13Pleschke J.M. Kleczkowska H.E. Strohm M. Althaus F.R. J. Biol. Chem. 2000; 275: 40974-40980Abstract Full Text Full Text PDF PubMed Scopus (464) Google Scholar). to be interact non-covalently with pADPr in Covalent or non-covalent modification to the site-specific DNA-binding activity of p53 or its transcriptional activity H. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, D.S. M. 2001; PubMed Scopus Google Scholar). PARP-1 activity may regulate other post-translational of p53 as or acetylation, in response to DNA damage. using two to PARP-1 we have that PARP-1 is a regulator of p53 transactivation function in response to ionizing radiation in both the cell and the cell The through PARP-1 the p53-mediated DNA damage response to be M. and J. H. for are to for with the activity

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