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BRCA Mutation and PARP Inhibitors
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Arjun Mittra, James H. Doroshow, Alice P. Chen
PAR is degraded by Poly (ADP-ribose) glycohydrolase and possibly ADP-ribose hydrolase 3, into ADP-ribose molecules, which are metabolized further to AMP. The increased AMP: ATP ratio catalyzes the metabolic sensor AMP-activated protein kinase (AMPKs). Mammalian target of rapamycin complex 1 (MTORC1) is thereby inhibited, inducing autophagy [50]. Thus, cellular energy homeostasis is regulated. In the process of making PAR, NAD+ is converted to nicotinamide. To replenish the NAD+ from nicotinamide, phosphoribosyl pyrophosphate and ATP are converted to AMP and pyrophosphate (Fig. 15.1). In the case of extreme DNA damage, as with ischemia, PARP 1 hyperactivation results in depletion of NAD+ and ATP, resulting in cell death by necrosis or apoptosis [108].
Irradiation-induced damage and the DNA damage response
Published in Michael C. Joiner, Albert J. van der Kogel, Basic Clinical Radiobiology, 2018
Conchita Vens, Marianne Koritzinsky, Bradly G. Wouters
As outlined previously, one of the initial lesion sensing events is the activation of PARP and the formation of PAR on chromatin at the lesion sites. SSBs and abasic sites cause a quick PAR response that facilitates repair protein recruitment. PAR polymers are then removed by poly (ADP-ribose)-glycohydrolase (PARG). An outline of the BER and SSBR events that follow is shown in Figure 2.7. Briefly, in BER, most of the damaged bases in the DNA will be detected and removed by specialized glycosylase proteins which remove the damaged base, resulting in an abasic site. This will be recognized by an AP endonuclease (APE), which will cut the DNA backbone leaving a nick, or SSB. Subsequent repair follows one of two pathways called short patch or long patch. In short patch, the damaged base is replaced by DNA polymerase β (POLβ) in the presence of XRCC1, followed by ligation of the DNA ends by ligase 3 (LIG3). In long patch, up to 10 nucleotides surrounding the damaged site are replaced by DNA polymerase δ or ε in the presence of PCNA, while Flap endonuclease 1 (FEN1) removes the overhanging nucleotides, followed by ligation by ligase 1 (LIG1).
Role of Nonhistone Chromosomal Proteins in Selective Gene Expression
Published in Gerald M. Kolodny, Eukaryotic Gene Regulation, 2018
I.R. Phillips, E.A. Shephard, J.L. Stein, G.S. Stein
The synthesis of acceptor-bound poly(ADP-ribose) is catalyzed from the ADP-ri-bosyl moiety of nicotinamide adenine dinucleotide (NAD) by poly(ADP-ribose) synthetase (or polymerase) which is tightly associated with chromatin. Some workers have found that the enzyme is preferentially associated with euchromatin,84 but others have not found this to be the case.85 The polymerization reaction exhibits an absolute requirement for DNA, and the presence of histones increases the average chain length but has no effect on chain number.86 The polymer is degraded by the chromatin-asso-ciated enzyme poly(ADP-ribose) glycohydrolase which cleaves the l′→2′-glycosidic bond between adjacent riboses to yield ADP-ribose.87
Advances in the treatment of platinum resistant epithelial ovarian cancer: an update on standard and experimental therapies
Published in Expert Opinion on Investigational Drugs, 2021
Shuk on Annie Leung, Panagiotis A. Konstantinopoulos
Following the approval of several PARP inhibitors, resistance has emerged in practice. Several mechanisms for resistance have been described in literature, including 1) increased drug efflux (e.g., overexpression of the multidrug resistance gene, ABCB1); 2) loss of PARP1 function due to mutation or deletion; 3) loss of PARG (poly [ADP-ribose] glycohydrolase) and restoration of PARylation; (4) stabilization of stalled forks; and 5) restoration of homologous repair (HR) function, which is by far the most common mechanism of PARPi resistance [30,31,32] whereby tumors switch from an HR-deficient to an HR-proficient state. The most common mechanism is through the restoration of the expression or function of key proteins in the HR pathway (i.e., BRCA1, BRCA2, RAD51C, and RAD51D) by the acquisition of secondary mutations, also known as ‘reversion mutations’, which can be detected in the tumor or circulating free DNA [33,34,35].
The development of PARP as a successful target for cancer therapy
Published in Expert Review of Anticancer Therapy, 2018
Roberto Ferrara, Francesca Simionato, Chiara Ciccarese, Elisabetta Grego, Sara Cingarlini, Roberto Iacovelli, Emilio Bria, Giampaolo Tortora, Davide Melisi
Beyond mutations, post-transcriptional gene regulation via RNA-binding proteins, may also drive resistance to PARPi, as recently reported in preclinical models of pancreatic cancer. Specifically, DNA damage can trigger the post-transcriptional activation of a poly ADP-ribose glycohydrolase (PARG), able to reduce PAR production and interfere with PARP1 trapping on DNA, consequently reducing the efficacy of PARPi [78].
PARP inhibitors as single agents and in combination therapy: the most promising treatment strategies in clinical trials for BRCA-mutant ovarian and triple-negative breast cancers
Published in Expert Opinion on Investigational Drugs, 2022
PARP is a family of proteins that comprise 17 members with diverse functions (Table 1) [16]. Only four PARPs generate poly-ADP-ribose (PAR) chains: PARP1, PARP2, and the two tankyrases, PARP5a and PARP5b, while the other PARPs add only a mono-ADP-ribose [17]. The most studied PARP proteins are PARP1, 2, and 3, involved in DNA damage repair. PARP1 is a DNA damage sensor protein and an enzyme that functions in an error-free, base excision repair pathway. Once single-strand breaks (SSB) occur, PARP1 binds to DNA through zinc finger domains, undergoes a conformational change, and synthesizes a polymetric adenosine diphosphate ribose (poly-ADP-ribose), also called PAR chains on itself (autoPARylation) or on DNA damage response proteins (PARylation) for repair single-strand breaks [18] (Figure 1). Meantime, the nicotinamide adenine dinucleotide (NAD+), a cofactor of PARP1, binds to the active site of the enzyme PARP1. These PAR chains lead to the recruitment of additional DNA repair effectors, such as a scaffolding protein XRCC1, to complete the DNA repair process [19]. After repairing, the PAR chains are degraded via Poly(ADP-ribose) glycohydrolase (PARG) and other proteins [20] (Figure 1). This PARylation of proteins around the DNA breaks also mediates DNA repair by modifying chromatin structure, such as histone-PARylation [21]. Pharmacological PARP inhibitors (PARPis) structurally mimic nicotinamide and have two general effects: (1) catalytic inhibition of PARP1/2 via preventing PARylation and (2) ‘trapping’ PARP1/2 on damaged DNA (Figure 1). Of note, the differential trapping potency does not correlate with the catalytic inhibitory properties for each drug [22]. The potency in trapping PARPs differs among inhibitors, with the highest potency reported for talazoparib, followed by niraparib, olaparib, and then veliparib [22–24] (Table 2). Even though the mechanisms of PARP trapping to stall the progression of replication forks are still unclear, the current hypothesis includes enhanced PARP1 and DNA binding avidity [22,23] and inhibited PARP1 release due to autoPARylation [25].