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

Memorial Sloan-Kettering Cancer Center, New York, New York, United States
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.

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Available from: Hediye Erdjument-Bromage, Apr 29, 2015
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    • "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]. "
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