Pleiotropic role of PARP1: an overview

Abstract

Poly (ADP-ribose) polymerase 1 (PARP1) protein is encoded by the PARP1 gene located on chromosome 1 (1q42.12) in human cells. It plays a crucial role in post-translational modification by adding poly (ADP-ribose) (PAR) groups to various proteins and PARP1 itself by utilizing nicotinamide adenine dinucleotide (NAD +) as a substrate. Since the discovery of PARP1, its role in DNA repair and cell death has been its identity. This is evident from an overwhelmingly high number of scientific reports in this regard. However, PARP1 also plays critical roles in inflammation, metabolism, tumor development and progression, chromatin modification and transcription, mRNA stability, and alternative splicing. In the present study, we attempted to compile all the scattered scientific information about this molecule, including the structure and multifunctional role of PARP1 in cancer and non-cancer diseases, along with PARP1 inhibitors (PARPis). Furthermore, for the first time, we have classified PARP1-mediated cell death for ease of understanding its role in cell death pathways.

Keywords: Cancer; Chromatin; DNA repair; PAR; PARP1; PARPis; Transcription.

Fig. 1

Structure of PARP1. Poly (ADP-ribose) polymerase 1 (PARP1) consists of three functional domains, namely the amino-terminal DNA binding domain, carboxy-terminal domain, and central auto modification domain. The DNA binding domain comprises three zinc finger domains ZI, ZII, and ZIII. The carboxy-terminal domain consists of a tryptophan-glycine-arginine rich (WGR) domain, the catalytic subdomain, and a PARP signature site

Fig. 2

Functions of PARP1. Poly (ADP-ribose) polymerase 1 (PARP1) modulates the gene expression by converting heterochromatin regions to euchromatin and hypomethylation of chromatin by inhibiting the DNA-methyltransferase 1 (DNMT1) protein. PARP1 also acts as a transcription factor and transcriptional coactivator by binding to transcription factors. The major function of PARP1 is to sense DNA damage and recruit DNA repair machinery. It also facilitates tumor formation and metastasis by activation Extracellular Regulated Kinase (ERK) and the c-Jun N-terminal kinase signaling pathway (JNK). PARP1 activates the Nuclear Factor kappa (NF-kB) transcription factor that activates the transcription of genes involved in inflammation and cancer cell survival (image created with Biorender.com)

Fig. 3

Role of PARP1 in mRNA regulation and cell death. Poly (ADP-ribose) polymerase 1 (PARP1) modulates alternative splicing and mRNA stability. The hyperactivation of PARP1 leads to Poly (ADP-ribose) (PAR) synthesis and its autoparylation. The PARs attached to PARP1 are released by poly (ADP-ribose) glycohydrolase (PARG), and it translocates to the cytosol. PAR mediates the release of apoptosis-inducing factor (AIF) attached to mitochondria in the parthanatos. In the case of apoptosis, caspase-3/7 cleaves off PARP1 into two fragments (89 kDa and 24 kDa) in the nucleus. The 89 kDa PAR attached fragment translocates to the cytoplasm, where it interacts with AIF attached to mitochondria by PAR and mediates its release. The common event shared by both parthanatos and apoptosis includes AIF translocation to the nucleus and mediates the DNA breakdown by recruiting DNAse (image created with Biorender.com)

Fig. 4

Classification of PARP1-mediated cell death. The classification of Poly (ADP-ribose) polymerase 1 (PARP1)-induced cell death based on the involvement of caspase (image created with Biorender.com)