Effects of ADP‐ribosylarginine Hydrolase (ARH1) on Cell Proliferation and Tumorigenesis

Abstract

Mono‐ADP‐ribosylation, a post‐translational modification involving the transfer of ADP‐ribose from NAD to an acceptor protein is regulated by enzymes that catalyze opposing arms of ADP‐ribosylation cycles. ADP‐ribosyltransferases (ARTs) catalyze the modification of ADP‐ribose acceptors, and ADP‐ribosyl‐acceptor hydrolases (ARHs) cleave the ADP‐ribose‐acceptor bond. ARH1 catalyzes for the hydrolysis of α‐ADP‐ribose‐(arginine)protein bonds formed by NAD:arginine ARTs. ARH1−/− cells grown from embryonic tissues of an ARH1 knockout mouse, and ARH1−/− cells transformed with an inactive, double‐mutant ARH1 gene (ARH1−/−+dm) had higher proliferation rates than wild‐type ARH1+/+ cells and ARH1−/− cells expressing the wild‐type ARH1 gene (ARH1−/−+wt). Like ARH1−/− cells, ARH1−/−+dm cells formed more colonies in soft agar than did ARH1+/+ cells or ARH1−/−+wt cells. Similarly, ARH1−/− and ARH1−/−+dm cells, but not ARH1+/+ and ARH1−/−+wt cells, produced tumors in nude mice. ARH1−/− mice also developed diverse tumors spontaneously more frequently than did their wild‐type littermates. As expected based on the function proposed for ARH1 in an ADP‐ribosylation cycle(s), basal ADP‐ribose‐arginine content of ARH1−/− cells and ARH1−/− mouse tissues was higher than those of wild‐type cells and tissues. Thus, tumorigenesis appears to be related to mono‐ADP‐ribosylation of arginine residues in proteins.