Mono(ADP-ribosyl)ation Enzymes and NAD+ Metabolism: A Focus on Diseases and Therapeutic Perspectives

Abstract

Mono(ADP-ribose) transferases and mono(ADP-ribosyl)ating sirtuins use NAD+ to perform the mono(ADP-ribosyl)ation, a simple form of post-translational modification of proteins and, in some cases, of nucleic acids. The availability of NAD+ is a limiting step and an essential requisite for NAD+ consuming enzymes. The synthesis and degradation of NAD+, as well as the transport of its key intermediates among cell compartments, play a vital role in the maintenance of optimal NAD+ levels, which are essential for the regulation of NAD+-utilizing enzymes. In this review, we provide an overview of the current knowledge of NAD+ metabolism, highlighting the functional liaison with mono(ADP-ribosyl)ating enzymes, such as the well-known ARTD10 (also named PARP10), SIRT6, and SIRT7. To this aim, we discuss the link of these enzymes with NAD+ metabolism and chronic diseases, such as cancer, degenerative disorders and aging.

The use of phosphorescence oxygen analyzer to measure the effects of rotenone and 1-methyl-4-phenylpyridinium on striatal cellular respiration in C57BL6 mice

“…The resulting reducing equivalent NADH then wires these electrons to NADH:ubiquinone oxidoreductase (dehydrogenation/oxidation), generating an electrochemical potential (electromotive force) across the inner mitochondrial membrane that drives ATP synthesis (phosphorylation). Consequently, inhibitors of NADH:ubiquinone oxidoreductase, such as rotenone and MPP+ are expected to deplete both NAD+ and ATP [ 16 , 17 ].…”

Adp-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control

“…Enzymes that erase in part or becoming unavailable for HPF1 interaction [18,19]. During the DNA damage repair, PARP1 and PARP2 modify serine residues [1], but also to a lesser extent tyrosine, lysine, and acidic residues [20]. Amino acid targets that can be modified include lysine (by PARP1, PARP3, ARTD10, ARTD11, and ARTD15/PARP16), aspartate and glutamate (by PARP1/2/3, ARTD8/PARP14, ARTD10, ARTD11, ARTD12, ARTD15/PARP16, ARTD17/PARP6), serine (PARP1/2), and cysteine (by ARTD11, ARTD12, ARTD17/PARP6); additional amino acids that can be modified are arginine and histidine [21][22][23][24].…”

“…ARTD8/PARP14 MARylates histone deacetylases HDAC2 and HDAC3, as well as TBK1, TANK (TRAF-associated NF-κB activator) binding kinase 1, involved in IRF3 activation and interferon signaling [116]. ARTD8 MARylates STAT1, leading to reduced STAT1 phosphorylation levels: this leads in macrophages to suppression of the IFNγ-STAT1 signaling and of the TNF-α/IL-β proinflammatory pathway [1]. New, potent ARTD8 inhibitors have been developed, such as H10, possessing more than 20-fold higher selectivity on ARTD8 in respect to PARP1 [117][118][119].…”

“…ARTD10 has tumor suppressor activity by inhibiting myc, and by MARylation of Aurora A kinase, inhibiting its phosphorylation on the same residue: The MARylation is exerted after interaction with the ubiquitin ligase RNF114, that ubiquitylates ARTD10, activating it; a loss of RNF114 in cancers (mutation, deletion, downregulation) may lead to loss in ARTD10 activity [1,130]. ARTD10 may have also oncogenic activity, being involved in some cancers, promoting proliferation and restart of stalled replication forks, alleviating cell survival during replication stress [1,145].…”

“…MAR hydrolases cleave the modifications promoted by ARTD10. MacroD2, expressed in neuroblastomas, and MacroD1, overexpressed in various cancers, can counteract the tumor suppressive role of ARTD10 [1,49]. MARylation of ARTD10 is recognized by ARTD8/PARP14, that is docked to the MAR structure to form a protein complex.…”