期刊
GENES & DEVELOPMENT
卷 26, 期 17, 页码 1972-1983出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.193193.112
关键词
mouse mammary tumor virus; progesterone receptor; transcriptional regulation; histone H1; PARP-1; chromatin remodeling
资金
- Departament d'Innovacio Universitat i Empresa (DIUiE), Ministerio de Educacion y Ciencia (MEC) [BMC 2003-02902, CSD2006-00049]
- Fondo de Investigacion Sanitaria (FIS) [PI0411605, CP04/00087]
- FEDER [BIO2008-0205]
- EU IP HEROIC
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.
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