Poly(ADP-ribose) Binds to Specific Domains of p53 and Alters Its DNA Binding Functions

Malanga, Maria; Pleschke, Jutta M.; Kleczkowska, Hanna E.; Althaus, Felix R.

doi:10.1074/jbc.273.19.11839

Cited by 203 publications

(156 citation statements)

References 26 publications

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“…Another possibility is that p53 interacts noncovalently with pADPr, either free or bound to nuclear protein acceptors such as PARP-1. Three regions within the tetramerization and DNA-binding domains have been found to interact with pADPr in vitro (14); these regions contain putative pADPr-binding sites as determined by sequence alignment analysis (13). It remains to be determined whether these regions interact non-covalently with pADPr in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…The oligomerization and DNA-binding domains of p53 contain copies of the recently characterized pADPr-binding site (13). Furthermore, pADPr has been shown to interact non-covalently with p53 in vitro (14), and p53 can be covalently poly(ADP-ribosyl)ated in vitro (15,16) and in osteosarcoma cells undergoing spontaneous apoptosis (17). Finally, recent studies show that poly(ADP-ribosyl)ation of p53 can interfere with its site-specific DNA-binding activity (18,19).…”

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confidence: 99%

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

Wieler

Gagné²,

Vaziri

et al. 2003

Journal of Biological Chemistry

103

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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 (1). DNA strand breaks produced by ionizing radiation (IR) 1 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. 2 and 3). Elevated levels of p53 protein are believed to be important to initiate the events that lead to G 1 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 (5Ј-PuPuPuC(A/T)(T/A)GPyPyPy-3Ј) separated by a spacer consisting of 0 -13 nucleotides (4). 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. 2 and 5).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 (6, 7), and ataxia telangiectasia-related kinase protein is involved in the activation of p53 in response to UV irradiation (8).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. 9 -11). 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 ϩ as substrate. During the process of poly(ADP-ribosyl)ation, NAD ϩ 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 ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Wieler

Gagné²,

Vaziri

et al. 2003

Journal of Biological Chemistry

103

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“…Poly(ADP-ribose) polymerase1 (PARP1), the main member of this family, hosts polymers in its central domain where 28 automodification sites are present; these sites have the glutamic acid necessary for the first link (Rolli et al, 2000). Apart from modifying covalently acceptor proteins, long and branched polymers are able to bind noncovalently to proteins with important functional roles (Althaus et al, 1995;Malanga et al, 1998;Pleschke et al, 2000); the polymers can be free or still bound to PARP1. Considering the chemical structure of polymers, they resemble nucleic acids with a great number of negative charges that modify the acceptor proteins.…”

Section: Introductionmentioning

confidence: 99%

Modulation of DNMT1 activity by ADP-ribose polymers

et al. 2005

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We provided evidence that competitive inhibition of poly(ADP-ribose) polymerases in mammalian cells treated with 3-aminobenzamide causes DNA hypermethylation in the genome and anomalous hypermethylation of CpG islands. The molecular mechanism(s) connecting poly(ADP-ribosyl)ation with DNA methylation is still unknown. Here we show that DNMT1 is able to bind long and branched ADP-ribose polymers in a noncovalent way. Binding of poly ADP-ribose on DNMT1 inhibits DNA methyltransferase activity. Co-immunoprecipitation reactions indicate that PARP1 and DNMT1 are associated in vivo and that in this complex PARP1 is present in its ADP-ribosylated isoform. We suggest that this complex is catalytically inefficient in DNA methylation.

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“…We have previously shown that the noncovalent binding of PAR to p53 (10) or members of the MARCKS protein family (11) may drastically alter several domain-specific functions of these proteins. Apart from its specificity, PAR binding to proteins is exceptionally strong.…”

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confidence: 99%