Abstract
PARP-1 activation by CDK2 stimulates chromatin remodeling and progesterone gene regulation.
Major finding: PARP-1 activation by CDK2 stimulates chromatin remodeling and progesterone gene regulation.
Mechanism: PARP-1 phosphorylation by CDK2 enhances PARylation and promotes histone H1 displacement.
Impact: PARP-1 may play a broader role in cancer gene regulation independent of DNA damage.
Transcriptional regulation is mediated in large part by posttranslational modifications of chromatin-remodeling enzymes. Wright and colleagues investigated the contribution of poly-(ADP-ribose) polymerase-1 (PARP-1)–driven chromatin modification in hormone-regulated gene expression in the absence of DNA damage, a known activator of PARP-1. Progestin treatment of breast cancer cells led to a rapid and transient increase in PARP-1 activity, as measured by poly-(ADP)-ribosylation (PARylation) of nuclear proteins, and decreased levels of the PARP-1 substrate NAD. In addition, hormone stimulation enhanced the expression of progesterone target genes and induced proliferation, and these effects were dependent on the progestin-driven increase in PARP-1 activity. Inhibition of cyclin-dependent kinase 2 (CDK2), a hormone-activated kinase that regulates progesterone target genes, significantly diminished PAR accumulation and PARP-1–stimulated gene expression in response to progestin, suggesting that CDK2 activates PARP-1. In support of this idea, CDK2 directly interacted with PARP-1 and promoted its phosphorylation at 2 serine residues, which generated a more accessible NAD binding site in structural models and enhanced PARP-1 catalytic activity. CDK2-mediated phosphorylation of PARP-1 was required for hormone-induced PARylation and gene expression; mutation of these residues to alanine prevented PARP-1 activation by CDK2, whereas phosphomimetic mutations constitutively activated PARP-1 and triggered target gene induction, suggesting that CDK2 and PARP-1 coordinately regulate hormonal gene expression. Indeed, inhibition of PARP-1 and CDK2 activity modulated a large percentage of progesterone-regulated genes, and chromatin immunoprecipitation experiments confirmed corecruitment of activated PARP-1 and CDK2 to the same gene promoters enriched in progesterone receptor binding sites. Furthermore, PARP-1 activity facilitated chromatin opening via PARylation and subsequent displacement of histone H1 from these hormone-regulated promoters. These results suggest that PARP-1 plays an important role in transcriptional regulation independent of DNA damage and that its activity may drive progesterone-induced proliferation in breast cancer.
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