CDK2-dependent activation of PARP-1 is required for hormonal gene regulation in breast cancer cells

Wright, Roni H.G.; Castellano, Giancarlo; Bonet Martínez, Jaume, 1982-; Le Dily, François; Font Mateu, Jofre, 1977-; Ballaré, Cecilia Julia; Nacht, A. Silvina; Soronellas, Daniel; Oliva Miguel, Baldomero; Beato, Miguel

doi:http://dx.doi.org/10.1101/gad.193193.112

CDK2-dependent activation of PARP-1 is required for hormonal gene regulation in breast cancer cells

Citation

Wright RH, Castellano G, Bonet J, Le Dily F, Font-Mateu J, Ballaré C et al. CDK2-dependent activation of PARP-1 is required for hormonal gene regulation in breast cancer cells. Genes & Development. 2012;26(17):1972-83. DOI: 10.1101/gad.193193.112

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.