Title:New Insights into the Roles of NAD+-Poly(ADP-ribose) Metabolism and Poly(ADP-ribose) Glycohydrolase
Volume: 17
Issue: 7
Author(s): Sei-ichi Tanuma, Akira Sato, Takahiro Oyama, Atsushi Yoshimori, Hideaki Abe and Fumiaki Uchiumi
Affiliation:
Keywords:
apoptosis, (ADP-R)n catabolism, ADPRPPL, cancer chemotherapy, NAD+ biosynthesis, NAD+-poly(ADP-ribose)
metabolism, PARG, PARP.
Abstract: Accumulating evidence has suggested the fundamental functions of NAD+-poly(ADPribose)
metabolism in cellular and physiological processes, including energy homeostasis, signal
transduction, DNA transaction, genomic stability and cell death or survival. The NAD+ biosynthesis
and poly(ADP-ribose) [(ADP-R)n] turnover are tightly controlled by several key enzymes, such as
nicotinamide phosphoribosyltransferase (NmPRT), nicotinamide mononucleotide adenylyltransferases (NMNATs),
poly(ADP-ribose) polymerase (PARP), poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribose pyrophosphorylase
(ADPRPPL). Many researches investigating the roles of these enzymes in cells have revealed the physiological and pathological
importance, and thereby the therapeutical values. Among these enzymes, the polymer degrading enzyme PARG
has not yet been intensively studied, because of the low cellular content, lack of cell-available PARG chemical inhibitors
and PARG genetic models. So, the biological roles of (ADP-R)n catabolism by PARG are still being elucidated as compared
to those of synthesis by PARP. However, recent studies delineate that PARG-dependent (ADP-R)n degradation is
critical for many pathological conditions, and thus PARG is an important target for chemical therapeutics for several diseases.
This review will present the recent progresses about the roles of NAD+-(ADP-R)n metabolism and the structures
and functions of PARG, with a focus on its role in DNA repair and cell death by apoptosis in relation to central regulatory
network, and the therapeutic potentials of PARG inhibitors in cancer chemotherapy.
