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


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.

SUBMITTER: Wright RH 

PROVIDER: S-EPMC3435499 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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

Wright Roni H G RH   Castellano Giancarlo G   Bonet Jaume J   Le Dily Francois F   Font-Mateu Jofre J   Ballaré Cecilia C   Nacht A Silvina AS   Soronellas Daniel D   Oliva Baldo B   Beato Miguel M  

Genes & development 20120901 17


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 incr  ...[more]

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