Abstract
Poly(ADP-ribosyl)ation (PARylation) is catalysed by poly(ADP-ribose) polymerases (PARPs, also known as ARTDs) and then rapidly removed by degrading enzymes. Poly(ADP-ribose) (PAR) is produced from PARylation and provides a delicate and spatiotemporal interaction scaffold for numerous target proteins. The PARylation system, consisting of PAR synthesizers and erasers and PAR itself and readers, plays diverse roles in the DNA damage response (DDR), DNA repair, transcription, replication, chromatin remodeling, metabolism, and cell death. Despite great efforts by scientists in biochemistry, cell and molecular biology, genetics, and pharmacology over the last five decades, the biology of PARPs and PARylation remains enigmatic. In this review, we summarize the current understanding of the biological function of PARP1 (ARTD1), the founding member of the PARP family, focusing on the inter-dependent or -independent nature of different functional domains of the PARP1 protein. We also discuss the readers of PAR, whose function may transduce signals and coordinate the cellular processes, which has recently emerged as a new research avenue for PARP biology. We aim to provide some perspective on how future research might disentangle the biology of PARylation by dissecting the structural and functional relationship of PARP1, a major effector of the PARPs family.
Highlights
Poly(ADP-ribosyl)ation (PARylation) is a concerted and dynamic process
We aim to provide some perspective on how future research might disentangle the biology of PARylation by dissecting the structural and functional relationship of PARP1, a major effector of the PARPs family
Removal of PAR from its substrates is a rapid event which is regulated by PAR-degrading enzymes, such as PARG glycohydrolase, ADP-ribose hydrolases (ARHs), macrodomain-containing ADP-ribose erasers, and ADP-ribosyl lyase [3,4,5]
Summary
Poly(ADP-ribosyl)ation (PARylation) is a concerted and dynamic process. Poly(ADP-ribose) polymerases (PARPs, known as ARTDs) catalyze the transfer of the ADPr unit from NAD+ to form a long and branched chain of negatively charged poly(ADP-ribose) (PAR) on specific amino acid residues (e.g., glutamates (E), lysine (K), arginine (R), serine (S), and aspartate (D)), on PARP1 itself and other acceptor proteins [1,2]. By cross-talking with DNA–PKcs, PARP1 is involved in C-NHEJ [9] Both PARP1 and PAR act as binding surfaces for numerous other proteins and regulate several cellular processes, such as DNA repair, transcription, cell death, chromatin remodeling, inflammation, metabolic regulation, cell cycle regulation, differentiation, proteasomal degradation, RNA processing, and modulation of tumor suppressor (see Reviews [6,7,8,11]). These studies highlight PARP1 as a multifaceted enzyme that modulates various sophisticated cellular processes, depending on cellular stressors, own interactors and its product PAR and, more importantly, under physiological conditions of a multiple cellular organism. This review will concentrate on an overview of biochemical and biological studies of PARP1, aiming to illustrate the contribution of PARP1 protein and its enzymatic product PAR, as well as PAR interactors in biological processes in vivo
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