ReviewTargeting poly(ADP-ribose) glycohydrolase to draw apoptosis codes in cancer
Graphical abstract
Introduction
Poly(ADP-ribosyl)ation (PARylation) is a dynamic post-translational modification of proteins catalyzed by members of the PARP family of enzymes and multiples of the PARG splice-variant isoforms in mammalian cells [1], [2], [3], [4], [5], [6], [7], [8], [9]. This unique protein modification uses NAD+ as a substrate. Studies over the past two decades have led to an expansion of our knowledge of the biological functions of PAR metabolism in many molecular, cellular and pathological processes. Our concept regarding the physiological significances of NAD+-(ADP-ribose)n metabolism is the fundamental regulation of DNA transaction (DNA repair, replication, recombination and transcription) and genome maintenance, and thereby the control of three fundamental cellular processes, cell proliferation, differentiation and apoptosis (Fig. 1) [8]. Furthermore, it plays important roles in aging, inflammation, cancer and other diseases in relation to energy metabolism.
PARylation of chromosomal proteins has been well studied in DNA repair processes [7], [8], [9], [10], [11], [12]. In DNA damage repair, PARP is recruited to the sites of DNA lesions and activated to polymerize ADP-ribose moiety of NAD+ to γ-carboxyl groups of the glutamic acid residues of acceptor proteins (Figs. 2, 3; Reaction a). The PAR acts as an important signal for recruitment of repair factors to the damaged sites allowing DNA repair. Before DNA repair can start, PAR needs to be degraded by PARG. In 1989, the novel catabolic pathway of PAR for the generation of ATP in nuclei has been discovered [13] (Fig. 3): ADP-ribose liberated from PAR by PARG (Reaction b) is converted to ATP and ribose-5-phosphate (R-5-P) by the action of ADP-ribose pyrophosphorylase (ADPRPPL) (Reaction c) near the sites of DNA damage. This nuclear ATP works for the driving-force of the DNA repair processes, such as DNA polymerization and ligation, and the maintenance of DNA replication apparatus during DNA repair [8], [13], [14], [15], [16], [17], [18]. These findings have provided new insights into the physiological function of PAR turnover.
Recently, PARP inhibitor olaparib was firstly approved for cancer treatment targeting advanced ovarian cancer associated with defective BRCA1/2 genes, in which PARP inhibitors act to promote synthetic lethality [19], [20], [21], [22], [23]. Accordingly, PARP inhibitors could kill homologous recombination repair (HRR) deficient cancer cells. Furthermore, PARP inhibitors have shown promise of good treatment for stroke, heart disease and inflammation [24], [25]. Thus, PARylation by PARP has received considerable attention. On the other hand, the study of de-PARylation catalyzed by PARG has been still limited and the biological significance remains less understood [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37]. However, in recent years, structural and genetic studies have been performed to gain an insight into the biological functions of PARG [38], [39], [40], [41], [42], [43], [44], [45]. Furthermore, PARG inhibitors are developing to facilitate the studies of the pathological roles of PARG and its therapeutic potential in various diseases, especially in cancer [46], [47], [48], [49], [50], [51], [52], [53], [54], [55].
Given the key roles of PARG in numerous physiological and pathological states, the potential benefit of targeting PARG for therapeutic purposes is considerably high [8], [9]. This review will present the recent progresses regarding the physiological functions of PAR catabolism catalyzed by PARG and the current knowledge of the synthetic lethality of PARG inhibitors and the development of novel PARG inhibitors for cancer chemotherapy.
Section snippets
Poly(ADP-ribose) is primarily for NAD+ reservoir
Poly(ADP-ribose) [PAR, (ADP-R)n] was discovered over 50 years ago [4], [5], [6]. The new field of biological science is still more expanded and now becomes important in medical science. PAR is synthesized from NAD+ substrate by the action of PARP family of enzymes, which are activated by DNA breaks having 3′-OH [1], [2], [3], [4], [5], [6]. This polymer has a unique structure of repeating ADP-ribose units derived from NAD+, with its size ranging from a few to approximately 200 ADP-ribose
Roles of poly(ADP-ribose) glycohydrolase in cell death
PARG was found to be encoded by a single gene in mammalian cells [69]. The Parg gene undergoes alternative splicing, which results in multiple PARG isoforms that have been suggested to be located in different organelles [70]. During apoptosis, like PARP-1 [71], PARG is cleaved into two C-terminal fragments (74 and 85 kDa) by caspase-3 [72]. Recently, the absence or knockdown of PARG has been shown to lead to decrease caspase activities [50]. Furthermore, ADP-ribose generated from PAR by PARG
Biological significance of poly(ADP-ribose) catabolism in DNA repair
DNA damaging events per day in cells in usual states are estimated to be approximately 10,000 sites [83]. With the apparent high turnover rate of NAD+ [14], [15], [84], [85], if PAR were responsible for most (85–90%) NAD+ consumption, PAR should relatively undergo rapid turnover. This allows precise regulation of acceptor protein’s functions and adequate control of cellular responses. Given the multitude of NAD+ consuming reactions, such as mono(ADP-ribosyl)ation, cyclic ADP-ribose formation
A new strategy for cancer chemotherapy targeting poly(ADP-ribose) glycohydrolase
Cancer cells are known to show an increased rate of DNA damage and defecting one or more DNA repair mechanisms [86]. So, inhibitors targeting the ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related protein (ATR) kinases involved in DNA double strand break repair are currently undergoing clinical evaluation [86], [87], [88]. Interestingly, PARP inhibitors have shown to be synthetic lethal in homologous recombination repair (HRR) deficient cancers, such as these mutant
Development of poly(ADP-ribose) glycohydrolase inhibitors
The dynamic metabolism of PAR suggests a closely coordinated mode of actions of PARP and PARG. However, the biological and physiological roles of PARG are still not well elucidated as compared with those of PARP. It has been reported that the degradation of PAR by PARG leads to remodeling chromatin structure during various DNA transaction, such as DNA repair, replication, recombination and transcription [14], [18], [41], [42], [63], [64], [91], [92], [93], [94], [95], [96], [97], [98], [99].
Concluding perspectives
The past two decades have brought a number of discoveries that have changed our understanding of the physiological significances of NAD+-poly(ADP-ribose) metabolism [8], [9]. Biochemical and cell biological studies on PAR turnover have provided fundamental evidence of the important roles of PARP and PARG in DNA repair, replication and cell death or survival. In cancer chemotherapy, PARP inhibitors, olaparib, niraparib and rucaparib, are already being used clinically in specific tumors,
Declaration of Competing Interest
None.
Acknowledgements
We thank Dr. Takashi Sugimura (National Cancer Center Research Institute), Dr. Masanao Miwa (Nagahama Institute of Bio-Science and Technology), Dr. Mitsuko Masutani (National Cancer Center Research Institute and Nagasaki University), Dr. Yoshiyuki Kanai (Choju Medical Institute, Fukushimura Hospital) and Dr. Akira Sato (Tokyo University of Science) for helpful discussions. We also thank the laboratory colleagues, Daisuke Ashizawa, Ryo Ota, Sachie Kanamaki, Yuka Kato, Mariko Kamioka, Shota Oba,
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