ADP-ribosylation signalling and human disease

Abstract

ADP-ribosylation (ADPr) is a reversible post-translational modification of proteins, which controls major cellular and biological processes, including DNA damage repair, cell proliferation and differentiation, metabolism, stress and immune responses. In order to maintain the cellular homeostasis, diverse ADP-ribosyl transferases and hydrolases are involved in the fine-tuning of ADPr systems. The control of ADPr network is vital, and dysregulation of enzymes involved in the regulation of ADPr signalling has been linked to a number of inherited and acquired human diseases, such as several neurological disorders and in cancer. Conversely, the therapeutic manipulation of ADPr has been shown to ameliorate several disorders in both human and animal models. These include cardiovascular, inflammatory, autoimmune and neurological disorders. Herein, we summarize the recent findings in the field of ADPr, which support the impact of this modification in human pathophysiology and highlight the curative potential of targeting ADPr for translational and molecular medicine.

Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases

“…PARP-1 is also involved in neurodegenerative diseases characterized by cytotoxic protein aggregates, including Parkinson's disease (PD) and Alzheimer's diseases (AD). In both diseases, PARP-1 is activated by and leads to the generation of ROS/RNS, DNA damage, cell death, and inflammation [116]. In PD human brain specimens, a significant increase of PARP-1 protein levels was revealed in dopaminergic neurons of the substantia nigra, associated with NF-κB nuclear translocation [117].…”

PARP1 (poly(ADP-ribose) polymerase 1)

“…PARP1 activation is known to be associated with the pathogenesis of several central nervous system disorders, including ischemia, neuroinflammation, and neurodegenerative diseases such as Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) (Martire, Mosca, & d'Erme, 2015;Palazzo, Mikolcevic, Mikoc, Ahel, 2019). Neurological disorders can be characterized by aggregation of cytotoxic proteins, enhanced levels of oxidative stress followed by DNA damage, PARP1 activation, and excess of cellular levels of PAR (Palazzo et al, 2019). For instance, in PD, intracellular monomericSNCA (alpha-synuclein) forms higher-ordered protein aggregates which can spread from cell to cell.…”

Fluctuations of Histone Chemical Modifications in Breast, Prostate, and Colorectal Cancer: An Implication of Phytochemicals as Defenders of Chromatin Equilibrium

“…Subsequently, the chromatin structure is influenced by a negative charge added to the histone [43]. ADP-ribosylation is catalyzed by ADP-ribosyltransferases (ARTs) [47], in which single or multiple ADP-ribose units are transferred from nicotinamide adenine dinucleotide to a target protein [48] with simultaneous release of nicotinamide [49]. Histones are considered as one of the most important acceptors of ADP-ribosylation [50].…”