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Supplying Muscle Machines with Energy
Published in Peter W. Hochachka, Muscles as Molecular and Metabolic Machines, 2019
All currently known Phosphagens are substituted phosphoguanidinum compounds. The two best studied systems are phosphocreatine (PCr) and phosphoarginine (PArg) [formed from creatine (Cr) and arginine (Arg) by creatine Phosphokinase (CPK) and arginine Phosphokinase (APK), respectively!. Creatine is formed from methionine, glycine, and arginine; in man, this occurs in liver and pancreas, while in some mammals, the first step occurs in the kidney and the second in the liver (Walker, 1979). Creatine is accumulated in skeletal muscles, myocardium, and brain, but apparently mechanisms controlling storage amounts are unknown, although feedback repression of synthesis in the liver may limit total availability at these sites (Walker, 1979). By standards of most metabolites, the total pool sizes of PCr + Cr are high (30 μmolg-1 or more in fast-twitch muscles and somewhat lower in slow muscles and heart). On short- and long-term basis, the amount of PCr available for high power output (burst work) seems to be controlled by hypertrophy, not by concentration adjustments, and this adaptation mechanism seems localized to fast-twitch muscles (Holloszy and Booth, 1976). This is not the case for PArg. It too can be stored at high concentrations (up to 50 μmol-1 in some species) in this case there seems to be a reasonable correlation between burst work capacities and the amount of PArg stored (De Zwaan, 1983).
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).
Molecular Imaging of Reporter Genes
Published in Michel M. J. Modo, Jeff W. M. Bulte, Molecular and Cellular MR Imaging, 2007
Keren Ziv, Dorit Granot, Vicki Plaks, Batya Cohen, Michal Neeman
Arginine kinase catalyzes the reversible phosphorylation of arginine, and when expressed in mammalian cells, this enzyme leads to the accumulation of PArg, which can be resolved by 31P spectroscopy even in the presence of PCr106 (Figure 11.1). The function of this enzyme is to provide a buffer for ATP, and thus overexpression could lead to changes in cellular energetics. Despite the expected effects, adenoviral infection of animals in the hind limb muscle led to no apparent biological effects. Specific signal due to PArg was persistant and visible many months after infection. The major advantage of arginine kinase is that the reaction product PArg can be found in mammalian tissues only when the transgenic enzyme is produced, and thus there is no background, while the substrates of the reaction are all ubiquitous, not requiring exogenous administration of any reporter probe.
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
Epigenetic modifications may be an alternative mechanism leading to PARPi resistance. For example, it was recently reported that loss of BRCA1 promoter methylation can restore the BRCA1 expression resulting in resistance to PARPi (rucaparib) in ovarian cancer [119]. Another study shows that hyperacetylation of 53BP1, similar to depletion of 53BP1, inhibits NHEJ and restores the HR DNA repair pathway leading to PARPi resistance in BRCA1-mutant cells [120]. In addition, phosphorylation of PARP1 at Tyr907, mediated by c-Met, increases PARP1 enzymatic activity and inhibits its binding to PARPi, thereby rendering cells resistant to PARPis [121]. In fact, the combination of c-Met inhibitor (crizotinib and foretinib) and PARPi (ABT-888 and AG014699) synergistically inhibit TNBC cells in vitro and TNBC xenograft models in vivo [121]. Furthermore, PAR glycohydrolase (PARG) has been identified as an alternative major resistance mechanism of PARPi using genetic screens and multi-omics analysis in BRCA2-mutant mouse mammary tumors. PARG depletion restores PAR formation and rescues the PARP1 pathway [122].
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].
Poly-ADP-ribose polymerases (PARPs) as a therapeutic target in the treatment of selected cancers
Published in Expert Opinion on Therapeutic Targets, 2019
Jarosław Przybycinski, Magdalena Nalewajska, Małgorzata Marchelek-Mysliwiec, Violetta Dziedziejko, Andrzej Pawlik
Alterations in PARG activity have recently been observed to be associated with resistance to PARP inhibitors. PARG is a PAR glycohydrolasean enzyme that degrades nuclear PAR. The loss of PARG activity is a major resistance factor in BRCA2-mutated mouse mammary tumors [102]. Another mechanism could be related to Schlafen 11 inhibition. Schlafen 11 expression has previously been linked to resistance mechanisms to other drugs, including topoisomerase 1 and 2 inhibitors and alkylating agents [96]. Cell lines deficient in Schlafen 11 are resistant to talazoparib, and this resistance occurs as a result of irreversible replication inhibition [103].