PARP1 Co-regulates EP300–BRG1-dependent transcription of genes involved in breast cancer cell proliferation and DNA repair

Abstract

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.

Publication DOI: https://doi.org/10.3390/cancers11101539
Divisions: College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences
College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine
College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences > Chronic and Communicable Conditions
Additional Information: © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Funding: Polish National Science Center, grant number DEC-2013/11/D/NZ2/00033; Ministry of Science and Higher Education (776/STYP/11/2016).
Uncontrolled Keywords: Brahma-related gene 1 (BRG1),Cancer cell,Gene transcription,Histone acetyltransferase p300 (EP300),Poly-ADP-ribose polymerase 1 (PARP1),Oncology,Cancer Research
Full Text Link:
Related URLs: https://www.mdp ... 6694/11/10/1539 (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2019-10-11
Accepted Date: 2019-10-05
Authors: Sobczak, Maciej
Pitt, Andrew R (ORCID Profile 0000-0003-3619-6503)
Spickett, Corinne M (ORCID Profile 0000-0003-4054-9279)
Robaszkiewicz, Agnieszka

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