Biochemical characterization of mono ADP ribosyl transferase activity of human sirtuin SIRT7 and its regulation.

SIRT7, an epigenetic modulator is related to several important cellular processes like aging, genome stability, and metabolism. The mechanistic and regulatory aspect of this enzyme needs to be explored. SIRT7 contains a conserved catalytic core with long flanking N- and C-terminal extensions. We find that the N terminus is involved in substrate binding, thus also in its dual enzyme activity i.e. deacetylation and ADP ribosylation. The C-terminus is not essential for its catalysis. Mutation of certain residues at the active site suggests that mono ADP-ribosylation and deacetylation are two distinct activities of SIRT7. In this study, we also find that the SIRT7 enzyme can specifically transfer a single moiety of ADP ribose on other nuclear proteins, with a preference for NAD⁺. For this, the ADPr transfer follows the enzymatic reaction mechanism. Nicotinamide and certain metal ions have a significant negative effect on this mono ADP ribosylation process. A comparison of these dual activities suggests SIRT7's preference for the mono ADPr transfer over its deacetylation of H3K18Ac. Mono ADP ribosylation in cells is often linked to different metabolic disease conditions. This kind of modification of transcription factors, p53 and ELK4 by SIRT7 may play a key role in maintaining the tumor phenotype. Thus, SIRT7 becomes an important therapeutic hotspot for drug designing against several diseases. Finally, we can also relate SIRT7 to the DNA repair process through ADP ribosylation of one of its key players, Here, SIRT7 positively regulates the activity.

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