PARP1 Co-Regulates EP300–BRG1-Dependent Transcription of Genes Involved in Breast Cancer Cell Proliferation and DNA Repair
1
Department of General Biophysics, Institute of Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland
2
School of Life & Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(10), 1539; https://doi.org/10.3390/cancers11101539
Received: 17 August 2019 / Revised: 24 September 2019 / Accepted: 5 October 2019 / Published: 11 October 2019
(This article belongs to the Special Issue PARPs, PAR and NAD Metabolism and Their Inhibitors in Cancer)
BRG1, an active subunit of the SWI/SNF chromatin-remodeling complex, enables the EP300-dependent transcription of proliferation and DNA repair genes from their E2F/CpG-driven promoters in breast cancer cells. In the current study, we show that BRG1–EP300 complexes are accompanied by poly-ADP-ribose polymerase 1 (PARP1), which emerges as the functional component of the promoter-bound multiprotein units that are capable of controlling gene expression. This enzyme is co-distributed with BRG1 at highly acetylated promoters of genes such as CDK4, LIG1, or NEIL3, which are responsible for cancer cell growth and the removal of DNA damage. ADP-ribosylation is necessary to maintain active transcription, since it ensures an open chromatin structure that allows high acetylation and low histone density. PARP1-mediated modification of BRG1 and EP300 does not affect the association of enzymes with gene promoters; however, it does activate EP300, which acetylates nucleosomes, leading to their eviction by BRG1, thus allowing mRNA synthesis. Although PARP1 was found at BRG1 positive/H3K27ac negative promoters of highly expressed genes in a transformed breast cancer cell line, its transcriptional activity was limited to genes simultaneously controlled by BRG1 and EP300, indicating that the ADP-ribosylation of EP300 plays a dominant role in the regulation of BRG1–EP300-driven transcription. In conclusion, PARP1 directs the transcription of some proliferation and DNA repair genes in breast cancer cells by the ADP-ribosylation of EP300, thereby causing its activation and marking nucleosomes for displacement by BRG1. PARP1 in rapidly dividing cells facilitates the expression of genes that confer a cancer cell phenotype. Our study shows a new mechanism that links PARP1 with the removal of DNA damage in breast cancer cells via the regulation of BRG1–EP300-dependent transcription of genes involved in DNA repair pathways.
Keywords:
poly-ADP-ribose polymerase 1 (PARP1), brahma-related gene 1 (BRG1), histone acetyltransferase p300 (EP300), gene transcription; cancer cell
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MDPI and ACS Style
Sobczak, M.; Pitt, A.R.; Spickett, C.M.; Robaszkiewicz, A. PARP1 Co-Regulates EP300–BRG1-Dependent Transcription of Genes Involved in Breast Cancer Cell Proliferation and DNA Repair. Cancers 2019, 11, 1539.
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