PARP-1 Determines Specificity in a Retinoid Signaling Pathway via Direct Modulation of Mediator

Department of Biochemistry, Howard Hughes Medical Institute, University of Medicine and Dentistry of New Jersey, 683 Hoes Lane, Piscataway, New Jersey 08854, USA.
Molecular Cell (Impact Factor: 14.02). 05/2005; 18(1):83-96. DOI: 10.1016/j.molcel.2005.02.034
Source: PubMed


We show that PARP-1 is indispensable to retinoic acid receptor (RAR)-mediated transcription from the RARbeta2 promoter in a highly purified, reconstituted transcription system and that RA-inducible expression of all RARbeta isoforms is abrogated in PARP-1(-/-) cells in vivo. Importantly, PARP-1 activity was independent of its catalytic domain. PARP-1 directly interacts with RAR and Mediator. Chromatin immunoprecipitation experiments confirmed the presence of PARP-1 and Mediator on RAR-responsive promoters in vivo. Importantly, Mediator was inactive (Cdk8+) under basal conditions but was activated (Cdk8-) upon induction. However, in PARP-1(-/-) cells, Mediator was retained in its inactive state (Cdk8+) upon induction consistent with the absence of gene expression. PARP-1 became dispensable for ligand-dependent transcription in a chromatin reconstituted transcription assay when Mediator was devoid of the Cdk8 module (CRSP). PARP-1 appears to function as a specificity factor regulating the RA-induced switch of Mediator from the inactive (Cdk8+) to the active (Cdk8-) state in RAR-dependent transcription.

Download full-text


Available from: Hediye Erdjument-Bromage, Apr 29, 2015
  • Source
    • "For example, it has been shown that poly(ADP-ribosyl)ation blocks the chromatin binding of KDM5B, a histone lysine demethylase acting on trimethyl lysine 4 of histone H3, and inhibits its activity [8]. Moreover, through its ability to interact with and to modify co-repressor and co-activator complexes, PARP-1 can function as an exchange factor that promotes the switch from gene repression to gene activation in response to certain signalling pathways [9], [10]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Poly(ADP-ribosyl)ation is a post-translational modification of various proteins and participates in the regulation of chromatin structure and transcription through complex mechanisms not completely understood. We have previously shown that PARP-1, the major family member of poly(ADP-ribose)polymerases, plays an important role in the cell cycle reactivation of resting cells by regulating the expression of Immediate Early Response Genes, such as c-MYC, c-FOS, JUNB and EGR-1. In the present work we have investigated the molecular mechanisms by which the enzyme induces c-MYC transcription upon serum stimulation of quiescent cells. We show that PARP-1 is constitutively associated in vivo to a c-MYC promoter region recognized as biologically relevant for the transcriptional regulation of the gene. Moreover, we report that serum stimulation causes the prompt accumulation of ADP-ribose polymers on the same region and that this modification is required for chromatin decondensation and for the exchange of negative for positive transcriptional regulators. Finally we provide evidence that the inhibition of PARP activity along with serum stimulation impairs c-MYC induction by preventing the proper accumulation of histone H3 phosphoacetylation, a specific chromatin mark for the activation of Immediate Early Response Genes. These findings not only suggest a novel strategy by which PARP-1 regulates the transcriptional activity of promoters but also provide new information about the complex regulation of c-MYC expression, a critical determinant of the transition from quiescence to proliferation.
    PLoS ONE 07/2014; 9(7):e102575. DOI:10.1371/journal.pone.0102575 · 3.23 Impact Factor
  • Source
    • "PARP plays a role in transcriptional regulation, histone modification and other epigenetic functions, such as the regulation of insulator activity in addition to DNA repair22232425262728. Thus, it is possible that PARP contributes to the active DNA demethylation via histone modification and/or transcriptional regulation in the PGCs. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In mammalian primordial germ cells (PGCs), DNA demethylation is indispensible for parental imprint erasure, which is a reprogramming process essential for normal developmental potential. Thus, it is important to elucidate how DNA demethylation occurs in each imprinted region in PGCs and to determine which DNA demethylation pathway, passive or active, essentially contributes to the erasure of the imprint. Here, we report that active DNA demethylation via a putative Poly(ADP-ribose) polymerase (PARP) pathway is involved in H19-DMR imprint erasure in PGCs, as shown by an in vivo small molecule inhibitor assay. To the best of our knowledge, this is the first direct demonstration of a DNA replication-independent active DNA demethylation pathway in the erasure process of genomic imprinting in PGCs in vivo. The data also suggest that active DNA demethylation plays a significant role in the complete erasure of paternal imprinting in the female germ line.
    Scientific Reports 01/2014; 4:3658. DOI:10.1038/srep03658 · 5.58 Impact Factor
  • Source
    • "Gene expression can be further regulated by direct interactions between PARP-1 and DNA elements or binding factors. PARP-1 acts as a promoter-specific switch at target genes, facilitating the release of inhibitory co-regulators and recruitment of stimulatory co-regulators (97, 98). PARP-1 binding of the NF-κB immediate upstream region (IUR) element activates transcription of CXCL1, which encodes melanoma growth stimulatory activity protein and is overexpressed in the progression of malignant melanoma (99). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Poly(ADP-ribose) polymerases (PARPs) are DNA-dependent nuclear enzymes that transfer negatively charged ADP-ribose moieties from cellular nicotinamide-adenine-dinucleotide (NAD(+)) to a variety of protein substrates, altering protein-protein and protein-DNA interactions. The most studied of these enzymes is poly(ADP-ribose) polymerase-1 (PARP-1), which is an excellent therapeutic target in cancer due to its pivotal role in the DNA damage response. Clinical studies have shown susceptibility to PARP inhibitors in DNA repair defective cancers with only mild adverse side effects. Interestingly, additional studies are emerging which demonstrate a role for this therapy in DNA repair proficient tumors through a variety of mechanisms. In this review, we will discuss additional functions of PARP-1 - including regulation of inflammatory mediators, cellular energetics and death pathways, gene transcription, sex hormone- and ERK-mediated signaling, and mitosis - and the role these PARP-1-mediated processes play in oncogenesis, cancer progression, and the development of therapeutic resistance. As PARP-1 can act in both a pro- and anti-tumor manner depending on the context, it is important to consider the global effects of this protein in determining when, and how, to best use PARP inhibitors in anticancer therapy.
    Frontiers in Oncology 11/2013; 3:290. DOI:10.3389/fonc.2013.00290
Show more