ADP-ribosylation

ADP-ribosylation is a post-translational modification of proteins involving the addition of one or more ADP-ribose moieties to a protein. This modification is catalyzed by a family of enzymes known as ADP-ribosyltransferases (ARTs). ADP-ribosylation can have various effects on the modified proteins, including altering their activity, interactions, localization, and stability, which in turn can affect numerous cellular processes such as DNA repair, gene expression, cell signaling, and apoptosis.

Mechanism

ADP-ribosylation involves the transfer of the ADP-ribose group from NAD+ to specific amino acids in target proteins. This reaction is catalyzed by ADP-ribosyltransferases, which can be broadly classified into two groups: the diphtheria toxin-like (ARTDs or PARPs) and the cholera toxin-like (ARTCs) families. The ARTDs are primarily involved in DNA damage response and cellular stress responses, with PARP1 being the most well-studied member. The ARTCs are usually found on the cell surface and are involved in modulating immune responses and cell-cell adhesion.

Types of ADP-ribosylation

ADP-ribosylation can be either mono-ADP-ribosylation (MARylation), where a single ADP-ribose is attached to the target protein, or poly-ADP-ribosylation (PARylation), where multiple ADP-ribose units form a chain. PARylation is particularly important in the context of DNA repair, where it serves as a signal for the recruitment of DNA repair proteins.

Biological Functions

ADP-ribosylation plays a critical role in various biological processes:

• In DNA repair, PARylation by PARP1 signals the presence of DNA breaks and recruits repair proteins.
• It regulates gene expression by modifying transcription factors and chromatin structure.
• It influences cell signaling pathways, including those involved in cell death and inflammation.
• In immune responses, ADP-ribosylation can modulate the activity of immune cells and the secretion of cytokines.

Pathological Implications

Dysregulation of ADP-ribosylation has been implicated in several diseases:

• Overactivation of PARP1 can lead to NAD+ depletion and cell death, contributing to the pathology of stroke, myocardial infarction, and neurodegeneration.
• Certain bacterial toxins, such as diphtheria toxin and cholera toxin, exploit ADP-ribosylation to inactivate host proteins, leading to disease.
• Aberrant ADP-ribosylation is also associated with cancer, as it can affect the stability and activity of proteins involved in cell proliferation and tumor suppression.

Therapeutic Implications

Given its role in DNA repair and cell death, targeting ADP-ribosylation, particularly PARP inhibitors, has emerged as a promising strategy in cancer therapy. PARP inhibitors are used to treat certain types of cancers by exploiting the concept of synthetic lethality, where the inhibition of PARP in cancer cells deficient in certain DNA repair pathways leads to cell death.

Conclusion

ADP-ribosylation is a crucial post-translational modification that impacts a wide range of cellular functions and has significant implications for health and disease. Understanding the mechanisms and effects of ADP-ribosylation continues to be an important area of research, with potential therapeutic applications in cancer and other diseases.