CDK2-dependent activation of PARP-1 is required for hormonal gene regulation in breast cancer cells
- Roni H.G. Wright1,
- Giancarlo Castellano1,
- Jaume Bonet2,
- Francois Le Dily1,
- Jofre Font-Mateu1,
- Cecilia Ballaré1,
- A. Silvina Nacht1,
- Daniel Soronellas1,
- Baldo Oliva2 and
- Miguel Beato1,3
- 1Centre de Regulació Genòmica (CRG), Barcelona E-08003, Spain;
- 2Structural Bioinformatics Laboratory (SBI), Universitat Pompeu Fabra (UPF), Barcelona E-08003, Spain
Abstract
Eukaryotic gene regulation implies that transcription factors gain access to genomic information via poorly understood processes involving activation and targeting of kinases, histone-modifying enzymes, and chromatin remodelers to chromatin. Here we report that progestin gene regulation in breast cancer cells requires a rapid and transient increase in poly-(ADP)-ribose (PAR), accompanied by a dramatic decrease of cellular NAD that could have broad implications in cell physiology. This rapid increase in nuclear PARylation is mediated by activation of PAR polymerase PARP-1 as a result of phosphorylation by cyclin-dependent kinase CDK2. Hormone-dependent phosphorylation of PARP-1 by CDK2, within the catalytic domain, enhances its enzymatic capabilities. Activated PARP-1 contributes to the displacement of histone H1 and is essential for regulation of the majority of hormone-responsive genes and for the effect of progestins on cell cycle progression. Both global chromatin immunoprecipitation (ChIP) coupled with deep sequencing (ChIP-seq) and gene expression analysis show a strong overlap between PARP-1 and CDK2. Thus, progestin gene regulation involves a novel signaling pathway that connects CDK2-dependent activation of PARP-1 with histone H1 displacement. Given the multiplicity of PARP targets, this new pathway could be used for the pharmacological management of breast cancer.
Keywords
- mouse mammary tumor virus
- progesterone receptor
- transcriptional regulation
- histone H1
- PARP-1
- chromatin remodeling
Footnotes
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↵3 Corresponding author
E-mail miguel.beato{at}crg.es
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.193193.112.
- Received March 30, 2012.
- Accepted July 11, 2012.
- Copyright © 2012 by Cold Spring Harbor Laboratory Press