ADP-Ribosylation — A PARful Regulator of the Cell

Posttranslational modification (PTM) is the process of tweaking a protein after it has been synthesized, typically by adding or removing components to amino acids in its structure or by proteolytic cleavage. This modifies the chemical properties of the protein, effectively altering its functionality and increasing protein diversity (Ramazi and Zahiri 2021).

Over 300 different types of PTM have been described to date and are crucial in a vast variety of biological processes. One of these PTM methods is adenosine diphosphate (ADP)-ribosylation (ADPr), in which one or multiple ADP-ribose units are transferred from the donor coenzyme nicotinamide adenine dinucleotide (NAD+) to the protein (Palazzo et al. 2019).

Recent technological advances have allowed the study of ADPr in greater detail, highlighting its key role in health and disease, and illuminating the possibility of targeting this mechanism as a therapeutic option (Suskiewicz et al. 2023).

In this blog, we explore the intricate role of ADPr in health and disease.

What a Difference a Molecule Makes

ADPr can rapidly change the fate of a cell in a time-dependent and reversible manner. Poly(ADP-ribose) polymerases (PARPs), the most well-studied of which is PARP1, catalyze the transfer of ADP-ribose units onto the target, whereas the removal of ADP-ribose is mediated by enzymes such as ADP-ribosyl-acceptor hydrolases (ARHs) and poly(ADP-ribose) glycohydrolase (PARG) (Rack et al. 2020).

While PARP1 function plays a critical role in basic physiological processes, such as the regulation of transcription, it also has a significant role in cellular stress responses (Palazzo et al. 2019).

PARP enzymes can recognize breaks in single- and double-stranded DNA, triggering the activation of the DNA damage response (DDR) pathway. The enzyme binds to the defective DNA and undergoes a conformational change, exposing the NAD+ binding site and enabling NAD+ hydrolysis. In this way, PARPs can steal ADP-ribose from NAD+ and attach it to themselves or the surrounding histones. Poly-ADP-ribose (PAR) chains act as flags, signaling to reader domains on key proteins and recruiting them to the party. For example, one such recruited player in DDR is a scaffold protein called XRCC1, which subsequently recruits factors, such as DNA ligase, that act to patch up and repair the damaged DNA (Duma and Ahel 2023).

However, excessive PARP activation can have the opposite effect and actually results in more damage. Too much PARylation will deplete the level of NAD+, which is crucial for the production of adenosine triphosphate (ATP), the main energy currency in the cell, leading to a form of mitochondria-associated cell death known as parthanatos (Zhang et al. 2014). Therefore, the ADPr pathway must be tightly regulated to repair DNA and avoid cell death.

With such a prominent role in the cellular stress response, it’s no surprise that PARPs, and specifically PARP1, have been heavily studied in the context of diseases, and that the modulation of ADPr has emerged as a potential therapeutic strategy to remedy these maladies.

Treatment OpPARtunities

One field in particular that benefits from PARP modulation is cancer research. A class of drugs known as PARP inhibitors (PARPis) are frequently used in the treatment of specific types of cancer.

The first approved PARPi, olaparib, was originally developed to treat advanced BRCA-mutated ovarian cancer. BRAC1/BRAC2 are involved in the homologous recombination repair (HRR) pathway, and mutations in these genes lead to an inability to repair DNA damage via this mechanism, causing an overreliance on alternative pathways, such as the base excision repair (BER) pathway. The BER pathway is dependent upon PARP activation; therefore, PARPis block the ability of cancer cells to repair damage to their DNA and, consequently, induce cell death specifically in troublesome cells (Zhu and Shi 2025).

Since then, three more PARPis, rucaparib, niraparib, and talazoparib, have been approved in the US and Europe, and more are in development. Additionally, the number of cancer types in which PARPis are effective has broadened, now including breast, prostate, and pancreatic cancers.

Interestingly, while PARPis are most successful in tumors with BRCA mutations, or mutations in alternative genes associated with DNA repair pathways, they have also shown efficacy in tumors without obvious repair defects (Mirza et al. 2016, Poveda et al. 2022). This highlights the potential for alternative, unknown mechanisms of action within this drug class.

Some research suggests that PARPis may also be effective in other conditions. PARP1 hyperactivation has been observed in a variety of disease states, including in myocardial sections from patients with circulatory shock and brain samples from patients who died of stroke or suffered from brain trauma. Additionally, increased PARylation has been evident in several autoimmune and inflammatory diseases (Palazzo et al. 2019).

Animal studies have demonstrated the promise of PARPis in many of these conditions. PARPis effectively mitigated the effects of cardiovascular disease and ischemic stroke in multiple animal studies, as well as significantly reducing the inflammation associated with immune-mediated disease models, such as colitis, allergic airway inflammation, rheumatoid arthritis, and experimental autoimmune encephalitis (Kim et al. 2025, Liu et al. 2022, Rosado et al. 2013).

These studies highlight the enormous potential of PARPis as a therapeutic option not just for various forms of cancer but perhaps also for cardiovascular, neurological, and immunological conditions. In order to uncover this potential, more research is needed to elucidate the full mechanisms of action of PARPis and the full extent of ADPr’s involvement in health and disease.