ADP-ribosylation
[1][2] It is a reversible post-translational modification that is involved in many cellular processes, including cell signaling, DNA repair, gene regulation and apoptosis.
At this time, Pierre Chambon and coworkers observed the incorporation of ATP into hen liver nuclei extract.
[7] After extensive studies on the acid insoluble fraction, several different research laboratories were able to identify ADP-ribose, derived from NAD+, as the incorporated group.
[8] The first appearance of mono(ADP-ribosyl)ation occurred a year later during a study of toxins: the diphtheria toxin of Corynebacterium diphtheriae was shown to be dependent on NAD+ in order for it to be completely effective,[9] leading to the discovery of enzymatic conjugation of a single ADP-ribose group by mono(ADP-ribosyl)transferase.
In this transfer reaction, the N-glycosidic bond of NAD+ that bridges the ADP-ribose molecule and the nicotinamide group is cleaved, followed by nucleophilic attack by the target amino acid side chain.
Mono(ADP-ribosyl)transferases commonly catalyze the addition of ADP-ribose to arginine side chains using a highly conserved R-S-EXE motif of the enzyme.
Next, the arginine side chain of the target protein then acts a nucleophile, attacking the electrophilic carbon adjacent to the oxonium ion.
In order for this step to occur, the arginine nucleophile is deprotonated by a glutamate residue on the catalyzing enzyme[disputed – discuss].
Another conserved glutamate residue forms a hydrogen bond with one of the hydroxyl groups on the ribose chain to further facilitate this nucleophilic attack.
However, many other ADP-ribose acceptor sites such as serine,[16][17] arginine,[18] cysteine,[19] lysine,[20] diphthamide,[21] phosphoserine,[22] and asparagine[23] have been identified in subsequent works.
Studies have shown poly(ADP-ribose) drives the translocation of the apoptosis inducing factor protein to the nucleus where it will mediate DNA fragmentation.
Overactivation of PARPs has led to a necrotic cell death regulated by the tumor necrosis factor protein.
[25] ADP-ribosylation can affect gene expression at nearly every level of regulation, including chromatin organization, transcription factor recruitment and binding, and mRNA processing.
PARP1, a poly-ADP ribose polymerase, has been shown to affect chromatin structure and promote changes in the organization of nucleosomes through modification of histones.
For example, PARP14, a mono (ADP-ribosyl)transferase, has been shown to affect STAT transcription factor binding.
Other (ADP-ribosyl)transferases have been shown to modify proteins that bind mRNA, which can cause silencing of that gene transcript.
The function of these modifications is still unknown, but it has been proposed that ADP-ribosylation modulates higher-order chromatin structure in efforts to facilitate more accessible sites for repair factors to migrate to the DNA damage.
This is important in carcinogenesis because it could lead to the selection of PARP1 deficient cells (but not depleted) due to their survival advantage during cancer growth.
The mechanism of action of a PARP1 inhibitor is to enhance the damage done by chemotherapy on the cancerous DNA by disallowing the reparative function of PARP1 in BRCA1/2 deficient individuals .
PARP14 is another ADP-ribosylating enzyme that has been well-studied in regards to cancer therapy targets; it is a signal transducer and activator of STAT6 transcription-interacting protein, and was shown to be associated with the aggressiveness of B-cell lymphomas.
[32] Bacterial ADP-ribosylating exotoxins (bAREs) covalently transfer an ADP-ribose moiety of NAD+ to target proteins of infected eukaryotes, to yield nicotinamide and a free hydrogen ion.
