Emerging roles of ADP-ribosyl-acceptor hydrolases (ARHs) in tumorigenesis and cell death pathways.

Biochem Pharmacol 2019 09 27;167:44-49. Epub 2018 Sep 27.

Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1590, USA. Electronic address:

Malignant transformation may occur in the background of post-translational modification, such as ADP-ribosylation, phosphorylation and acetylation. Recent genomic analysis of ADP-ribosylation led to the discovery of more than twenty ADP-ribosyltransferases (ARTs), which catalyze either mono- or poly-ADP-ribosylation. ARTs catalyze the attachment of ADP-ribose to acceptor molecules. The ADP-ribose-acceptor bond can then be cleaved by a family of hydrolases in a substrate-specific manner, which is dependent on the acceptor and its functional group, e.g., arginine (guanidino), serine (hydroxyl), aspartate (carboxyl). These hydrolases vary in structure and function, and include poly-ADP-ribose glycohydrolase (PARG), MacroD1, MacroD2, terminal ADP-ribose protein glycohydrolase 1 (TARG1) and ADP-ribosyl-acceptor hydrolases (ARHs). In murine models, PARG deficiency increased susceptibility to alkylating agents-induced carcinogenesis. Similarly, by cleaving mono-ADP-ribosylated arginine on target proteins, ARH1 appears to inhibit tumor formation, suggesting that ARH1 is a tumor-suppressor gene. Although ARH3 is similar to ARH1 in amino acid sequence and crystal structure, ARH3 does not cleave ADP-ribose-arginine, rather it degrades in an exocidic manner, the PAR polymer and cleaves O-acetyl-ADP-ribose (OAADPr) and the ADP-ribose-serine linkage in acceptor proteins. Under conditions of oxidative stress, ARH3-deficient cells showed increased cytosolic PAR accumulation and PARP-1 mediated cell death. These findings expand our understanding of ADP-ribosylation and provide new therapeutic targets for cancer treatment. In the present review, research on ARH1-regulated tumorigenesis and cell death pathways that are enhanced by ARH3 deficiency are discussed.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bcp.2018.09.028DOI Listing
September 2019

Publication Analysis

Top Keywords

cell death
12
hydrolases arhs
8
arts catalyze
8
adp-ribosyl-acceptor hydrolases
8
death pathways
8
tumorigenesis cell
8
poly-adp-ribose glycohydrolase
4
glycohydrolase parg
4
cytosolic par
4
include poly-adp-ribose
4
acid sequence
4
par accumulation
4
function include
4
arh3-deficient cells
4
parg macrod1
4
adp-ribose protein
4
macrod2 terminal
4
cells increased
4
macrod1 macrod2
4
structure function
4

Similar Publications