ADP-ribosylaatio

Transcriptional Gene Regulation in Health and Disease

Delphine Quénet, in International Review of Cell and Molecular Biology, 2018

3.4 ADP-Ribosylation

ADP-ribosylation is a reaction catalyzed by most of members of the poly(ADP-ribose) polymerase (PARP) family, that is composed of 17 proteins in human (Barkauskaite et al., 2015). With the exception of PARP9 and PARP13, PARP proteins transfer a single mono-ADP-ribose group from NAD⁺ to their target proteins on arginine, aspartate, glutamate, lysine, and serine residues. PARP1–5 can add additional ADP-ribose units to generate a long negatively charged polymer (PAR, up to 200 units) (D'Amours et al., 1999). The degradation of the polymer may involve several enzymatic activities. Poly(ADP-ribose) glycohydrolase (PARG) cleaves the O-glycosidic ribose bond between the first ADP-ribose and the PAR chain (Brochu et al., 1994; Slade et al., 2011). Then, the final mono-ADP-ribose is cleaved by MacroD1 and MacroD2 (Jankevicius et al., 2013; Rosenthal et al., 2013; Sharifi et al., 2013). TARG1 (terminal ADP-ribose glycohydrolase 1/C6orf130) can either release the PAR or the final mono-ADP-ribose by a nucleophile attack (Sharifi et al., 2013).

Three domains recognize and bind to PAR chain: the poly(ADP-ribose)-binding zinc finger (PBZ), WWE domain, and the macrodomain (Barkauskaite et al., 2015). The macrodomain is found in numerous proteins, including PARP9/14/15 and the histone variant macroH2A. Interestingly, PARG, MacroD1, MacroD2, and TARG1 also contain a macrodomain which evolves to become their catalytic site.

This PTM is well described for its role in promoting DNA repair (Martin-Hernandez et al., 2017). During this process, ADP-ribosylation of chromatin leads to chromatin reorganization, recruitment of the DNA repair machinery, and regulation of gene expression (Tallis et al., 2014). It is noteworthy that ADP-ribosylation also occurs in the absence of DNA damage, suggesting a broad function of this PTM in physiological and pathological conditions.