title: 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.
authors.affiliation: Centre de Regulació Genòmica, Barcelona E-08003, Spain.
authors.forename: Roni H G
authors.initials: RH
authors.lastname: Wright
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Castellano
authors.forename: Jaume
authors.initials: J
authors.lastname: Bonet
authors.forename: Francois
authors.initials: F
authors.lastname: Le Dily
authors.forename: Jofre
authors.initials: J
authors.lastname: Font-Mateu
authors.forename: Cecilia
authors.initials: C
authors.lastname: Ballaré
authors.forename: A Silvina
authors.initials: AS
authors.lastname: Nacht
authors.forename: Daniel
authors.initials: D
authors.lastname: Soronellas
authors.forename: Baldo
authors.initials: B
authors.lastname: Oliva
authors.forename: Miguel
authors.initials: M
authors.lastname: Beato
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D010766:Phosphorylation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011372:Progestins / Q000494:pharmacology; D017434:Protein Structure, Tertiary
chemical_list: D011372:Progestins; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2