ADP‐ribosyltransferases, an update on function and nomenclature

FEBS Journal, Год журнала: 2021, Номер 289(23), С. 7399 - 7410

Опубликована: Июль 29, 2021

ADP‐ribosylation, a modification of proteins, nucleic acids, and metabolites, confers broad functions, including roles in stress responses elicited, for example, by DNA damage viral infection is involved intra‐ extracellular signaling, chromatin transcriptional regulation, protein biosynthesis, cell death. ADP‐ribosylation catalyzed ADP‐ribosyltransferases (ARTs), which transfer ADP‐ribose from NAD + onto substrates. The modification, occurs as mono‐ or poly‐ADP‐ribosylation, reversible due to the action different ADP‐ribosylhydrolases. Importantly, inhibitors ARTs are approved being developed clinical use. Moreover, ADP‐ribosylhydrolases assessed therapeutic targets, foremost antiviral drugs oncological indications. Due development novel reagents major technological advances that allow study unprecedented detail, an increasing number cellular processes pathways identified regulated ADP‐ribosylation. In addition, characterization biochemical structural aspects their catalytic activities have expanded our understanding this family. This increased knowledge requires common nomenclature be used describe relevant enzymes. Therefore, viewpoint, we propose updated broadly supported mammalian will facilitate future discussions when addressing biochemistry biology combined with brief description main functions illustrate diversity poly‐ADP‐ribose mediated processes.

Язык: Английский

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Cellular functions of the protein kinase ATM and their relevance to human disease

Nature Reviews Molecular Cell Biology, Год журнала: 2021, Номер 22(12), С. 796 - 814

Опубликована: Авг. 24, 2021

Язык: Английский

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The expanding universe of PARP1-mediated molecular and therapeutic mechanisms

Molecular Cell, Год журнала: 2022, Номер 82(12), С. 2315 - 2334

Опубликована: Март 9, 2022

Язык: Английский

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Alternate therapeutic pathways for PARP inhibitors and potential mechanisms of resistance

Experimental & Molecular Medicine, Год журнала: 2021, Номер 53(1), С. 42 - 51

Опубликована: Янв. 1, 2021

Homologous recombination (HR) repair deficiency impairs the proper maintenance of genomic stability, thus rendering cancer cells vulnerable to loss or inhibition DNA proteins, such as poly(ADP-ribose) polymerase-1 (PARP-1). Inhibitors nuclear PARPs are effective therapeutics for a number different types cancers. Here we review key concepts and current progress on therapeutic use PARP inhibitors (PARPi). PARPi selectively induce synthetic lethality in with homologous deficiencies (HRDs), most notable being harboring mutations BRCA1 BRCA2 genes. Recent clinical evidence, however, shows that can be regardless BRCA1/2 HRD status, suggesting broader population patients might benefit from therapy. Currently, four have been approved by Food Drug Administration (FDA) treatment advanced ovarian breast deleterious BRCA mutations. Although shown improve progression-free survival, inevitably develop resistance, which poses significant obstacle prolonged inhibitors. For example, somatic reversion often identified BRCA1/2-mutated cancers after platinum-based therapy, causing restoration HR capacity conferring resistance. Accordingly, studied combination other targeted therapies overcome enhance efficacy, sensitize tumors inhibition. Moreover, multiple trials now actively underway evaluate novel combinations anticancer PARPi-resistant cancer. In this review, highlight mechanisms action without defects provide an overview ongoing PARPi. We also PARPi-based strategies inhibitor

Язык: Английский

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ADP-ribosylation from molecular mechanisms to therapeutic implications

Cell, Год журнала: 2023, Номер 186(21), С. 4475 - 4495

Опубликована: Окт. 1, 2023

ADP-ribosylation is a ubiquitous modification of biomolecules, including proteins and nucleic acids, that regulates various cellular functions in all kingdoms life. The recent emergence new technologies to study has reshaped our understanding the molecular mechanisms govern establishment, removal, recognition this modification, as well its impact on organismal function. These advances have also revealed intricate involvement human physiology pathology enormous potential their manipulation holds for therapy. In review, we present state-of-the-art findings covering work structural biology, biochemistry, cell clinical aspects ADP-ribosylation.

Язык: Английский

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Axonal energy metabolism, and the effects in aging and neurodegenerative diseases

Molecular Neurodegeneration, Год журнала: 2023, Номер 18(1)

Опубликована: Июль 20, 2023

Abstract Human studies consistently identify bioenergetic maladaptations in brains upon aging and neurodegenerative disorders of (NDAs), such as Alzheimer’s disease, Parkinson’s Huntington’s Amyotrophic lateral sclerosis. Glucose is the major brain fuel glucose hypometabolism has been observed regions vulnerable to NDAs. Many susceptible are topological central hub connectome, linked by densely interconnected long-range axons. Axons, key components have high metabolic needs support neurotransmission other essential activities. Long-range axons particularly injury, neurotoxin exposure, protein stress, lysosomal dysfunction, etc. Axonopathy often an early sign neurodegeneration. Recent ascribe axonal maintenance failures local dysregulation. With this review, we aim stimulate research exploring metabolically oriented neuroprotection strategies enhance or normalize bioenergetics NDA models. Here start summarizing evidence from human patients animal models reveal correlation between connectomic disintegration aging/NDAs. To encourage mechanistic investigations on how dysregulation occurs during aging/NDAs, first review current literature distinct subdomains: axon initial segments, myelinated arbors harboring pre-synaptic boutons. In each subdomain, focus organization, activity-dependent regulation system, external glial support. Second, mechanisms regulating nicotinamide adenine dinucleotide (NAD + ) homeostasis, molecule for energy metabolism processes, including NAD biosynthetic, recycling, consuming pathways. Third, highlight innate vulnerability connectome discuss its perturbation As deficits developing into NDAs, especially asymptomatic phase, they likely exaggerated further impaired energetic cost neural network hyperactivity, pathology. Future interrogating causal relationship vulnerability, axonopathy, amyloid/tau pathology, cognitive decline will provide fundamental knowledge therapeutic interventions.

Язык: Английский

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The SARS-CoV-2 Conserved Macrodomain Is a Mono-ADP-Ribosylhydrolase

Journal of Virology, Год журнала: 2020, Номер 95(3)

Опубликована: Ноя. 9, 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-related CoVs encode 3 tandem macrodomains within nonstructural protein (nsp3). The first macrodomain, Mac1, is conserved throughout binds to hydrolyzes mono-ADP-ribose (MAR) from target proteins. Mac1 likely counters host-mediated antiviral ADP-ribosylation, a posttranslational modification that part of the host response viral infections. essential for pathogenesis in multiple animal models CoV infection, implicating it as virulence factor potential therapeutic target. Here, we report crystal structure SARS-CoV-2 complex with ADP-ribose. SARS-CoV-2, SARS-CoV, Middle East (MERS-CoV) domains exhibit similar structural folds, all proteins bound ADP-ribose affinities low micromolar range. Importantly, using ADP-ribose-detecting binding reagents both gel-based assay novel enzyme-linked immunosorbent assays (ELISAs), demonstrated de-MARylating activity proteins, leading more rapid loss substrate than others. In addition, none these enzymes could hydrolyze poly-ADP-ribose. We conclude are MAR-hydrolases functions, indicating compounds targeting may have broad anti-CoV activity.IMPORTANCE has recently emerged into human population led worldwide pandemic COVID-19 caused 1.2 million deaths worldwide. With no currently approved treatments, strategies desperately needed. All coronaviruses highly macrodomain (Mac1) removes adducts dynamic process increasingly being recognized an important regulates infection. be Thus, understanding its biochemistry enzyme critical steps efforts. describe hydrolysis activities direct comparison those SARS-CoV MERS-CoV These results step design testing therapies this unique domain.

Язык: Английский

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Unrestrained poly-ADP-ribosylation provides insights into chromatin regulation and human disease

Molecular Cell, Год журнала: 2021, Номер 81(12), С. 2640 - 2655.e8

Опубликована: Май 20, 2021

ARH3/ADPRHL2 and PARG are the primary enzymes reversing ADP-ribosylation in vertebrates, yet their functions vivo remain unclear. ARH3 is only hydrolase able to remove serine-linked mono(ADP-ribose) (MAR) but much less efficient than against poly(ADP-ribose) (PAR) chains vitro. Here, by using ARH3-deficient cells, we demonstrate that endogenous MARylation persists on chromatin throughout cell cycle, including mitosis, surprisingly well tolerated. Conversely, persistent PARylation highly toxic has distinct physiological effects, particular active transcription histone marks such as H3K9ac H3K27ac. Furthermore, reveal a synthetic lethal interaction between identify loss of mechanism PARP inhibitor resistance, both which can be exploited cancer therapy. Finally, extend our findings neurodegeneration, suggesting patients with inherited deficiency suffer from stress-induced pathogenic increase mitigated inhibition.

Язык: Английский

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Emerging role of PARP‐1 and PARthanatos in ischemic stroke

Journal of Neurochemistry, Год журнала: 2021, Номер 160(1), С. 74 - 87

Опубликована: Июль 9, 2021

Cell death is a key feature of neurological diseases, including stroke and neurodegenerative disorders. Studies in variety ischemic/hypoxic mouse models demonstrate that poly(ADP-ribose) polymerase 1 (PARP-1)-dependent cell death, also named PARthanatos, plays pivotal role ischemic neuronal disease progress. PARthanatos has its unique triggers, processors, executors convey highly orchestrated programmed signaling cascade. In addition to gene transcription, DNA damage repair, energy homeostasis through PARylation various targets, PARP-1 activation neuron glia attributes brain following ischemia/reperfusion. Pharmacological inhibition or genetic deletion reduces infarct volume, eliminates inflammation, improves recovery functions stroke. Here, we reviewed the their therapeutic potential.

Язык: Английский

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ADP-ribosylation of RNA and DNA: fromin vitrocharacterization toin vivofunction

Nucleic Acids Research, Год журнала: 2021, Номер 49(7), С. 3634 - 3650

Опубликована: Фев. 18, 2021

The functionality of DNA, RNA and proteins is altered dynamically in response to physiological pathological cues, partly achieved by their modification. While the modification with ADP-ribose has been well studied, nucleic acids were only recently identified as substrates for ADP-ribosylation mammalian enzymes. DNA can be ADP-ribosylated specific ADP-ribosyltransferases such PARP1-3, PARP10 tRNA 2'-phosphotransferase (TRPT1). Evidence suggests that these enzymes display different preferences towards oligonucleotides. These reactions are reversed ADP-ribosylhydrolases macrodomain ARH families, MACROD1, TARG1, PARG, ARH1 ARH3. Most findings derive from vitro experiments using recombinant components, leaving relevance this cells unclear. In Survey Summary, we provide an overview ADP-ribosylate acids, reversing hydrolases, substrates' requirements. Drawing on data available other organisms, pierisin1 cabbage butterflies bacterial toxin-antitoxin system DarT-DarG, discuss possible functions acid mammals. Hypothesized roles include damage repair, antiviral immunity or non-conventional cap. Lastly, assess various methods potentially suitable future studies ADP-ribosylation.

Язык: Английский

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