PARP1: Liaison of Chromatin Remodeling and Transcription

SIMPLE SUMMARY: Poly(ADP-ribose) polymerase 1 (PARP1) is perhaps the most studied member of the PARP superfamily and participates in numerous cellular processes. PARP1 inhibitors have been approved as drugs to treat various cancers in clinics, based on its role in DNA repair. Yet, there is a growing body of evidence showing multitasking function of PARP1 in regulation of gene expression. In this review article, we discuss the current knowledge of PARP1 and its conducted enzymatic process, i.e., PARylation, with an emphasis on gene expression by the interaction with transcription factors and regulation of chromatin conformation, dependent or independent of DNA damage. The molecular action mode of PARP1 in gene transcription may present as a potential target for therapeutic intervention of inflammation-related diseases and also for cancer therapy. ABSTRACT: Poly(ADP-ribosyl)ation (PARylation) is a covalent post-translational modification and plays a key role in the immediate response of cells to stress signals. Poly(ADP-ribose) polymerase 1 (PARP1), the founding member of the PARP superfamily, synthesizes long and branched polymers of ADP-ribose (PAR) onto acceptor proteins, thereby modulating their function and their local surrounding. PARP1 is the most prominent of the PARPs and is responsible for the production of about 90% of PAR in the cell. Therefore, PARP1 and PARylation play a pleotropic role in a wide range of cellular processes, such as DNA repair and genomic stability, cell death, chromatin remodeling, inflammatory response and gene transcription. PARP1 has DNA-binding and catalytic activities that are important for DNA repair, yet also modulate chromatin conformation and gene transcription, which can be independent of DNA damage response. PARP1 and PARylation homeostasis have also been implicated in multiple diseases, including inflammation, stroke, diabetes and cancer. Studies of the molecular action and biological function of PARP1 and PARylation provide a basis for the development of pharmaceutic strategies for clinical applications. This review focuses primarily on the role of PARP1 in the regulation of chromatin remodeling and transcriptional activation.