PARP7 and Mono-ADP-Ribosylation Negatively Regulate Estrogen Receptor α Signaling in Human Breast Cancer Cells
- Cells. 2021 Mar 11;10(3):623. doi: 10.3390/cells10030623.
- 1. Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Sognsvannsveien 9, 0372 Oslo, Norway.
- 2. Department of Pharmacology and Toxicology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
- 3. Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Blindernveien 31, 0371 Oslo, Norway.
ADP-ribosylation is a post-translational protein modification catalyzed by a family of proteins known as poly-ADP-ribose polymerases. PARP7 (TIPARP; ARTD14) is a mono-ADP-ribosyltransferase involved in several cellular processes, including responses to hypoxia, innate immunity and regulation of nuclear receptors. Since previous studies suggested that PARP7 was regulated by 17β-estradiol, we investigated whether PARP7 regulates Estrogen receptor α signaling. We confirmed the 17β-estradiol-dependent increases of PARP7 mRNA and protein levels in MCF-7 cells, and observed recruitment of Estrogen receptor α to the promoter of PARP7. Overexpression of PARP7 decreased ligand-dependent Estrogen receptor α signaling, while treatment of PARP7 knockout MCF-7 cells with 17β-estradiol resulted in increased expression of and recruitment to Estrogen receptor α target genes, in addition to increased proliferation. Co-immunoprecipitation assays revealed that PARP7 mono-ADP-ribosylated Estrogen receptor α, and mass spectrometry mapped the modified peptides to the receptor's ligand-independent transactivation domain. Co-immunoprecipitation with truncated Estrogen receptor α variants identified that the hinge region of the receptor is required for PARP7-dependent mono-ADP-ribosylation. These results imply that PARP7-mediated mono-ADP-ribosylation may play an important role in Estrogen receptor positive breast Cancer.