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16 pages, 2388 KB

Open AccessReview

Targeting the PARylation-Dependent Ubiquitination Signaling Pathway for Cancer Therapies

by Daoyuan Huang, Jingchao Wang, Li Chen, Weiwei Jiang, Hiroyuki Inuzuka, David K. Simon and Wenyi Wei

Biomolecules 2025, 15(2), 237; https://doi.org/10.3390/biom15020237 - 7 Feb 2025

Cited by 7 | Viewed by 3080

Abstract

Poly(ADP-ribosyl)ation (PARylation) is a dynamic protein post-translational modification (PTM) mediated by ADP-ribosyltransferases (ARTs), which regulates a plethora of essential biological processes, such as DNA repair, gene expression, and signal transduction. Among these, PAR-dependent ubiquitination (PARdU) plays a pivotal role in tagging PARylated substrates for subsequent ubiquitination and degradation events through the coordinated action of enzymes, including the E3 ligase RNF146 and the ADP-ribosyltransferase tankyrase. Notably, this pathway has emerged as a key regulator of tumorigenesis, immune modulation, and cell death. This review elucidates the molecular mechanisms of the PARdU pathway, including the RNF146–tankyrase interaction, substrate specificity, and upstream regulatory pathways. It also highlights the biological functions of PARdU in DNA damage repair, signaling pathways, and metabolic regulation, with a focus on its therapeutic potential in cancer treatment. Strategies targeting PARdU, such as tankyrase and RNF146 inhibitors, synthetic lethality approaches, and immune checkpoint regulation, offer promising avenues for precision oncology. These developments underscore the potential of PARdU as a transformative therapeutic target in combating various types of human cancer. Full article

(This article belongs to the Special Issue Bioactive Molecules: Structures, Functions and Potential Uses for Cancer Prevention and Targeted Therapies (2nd Edition))

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24 pages, 1538 KB

Open AccessReview

Drug Discovery Targeting Post-Translational Modifications in Response to DNA Damages Induced by Space Radiation

by Dafei Xie, Qi Huang and Pingkun Zhou

Int. J. Mol. Sci. 2023, 24(8), 7656; https://doi.org/10.3390/ijms24087656 - 21 Apr 2023

Cited by 8 | Viewed by 6243

Abstract

DNA damage in astronauts induced by cosmic radiation poses a major barrier to human space exploration. Cellular responses and repair of the most lethal DNA double-strand breaks (DSBs) are crucial for genomic integrity and cell survival. Post-translational modifications (PTMs), including phosphorylation, ubiquitylation, and SUMOylation, are among the regulatory factors modulating a delicate balance and choice between predominant DSB repair pathways, such as non-homologous end joining (NHEJ) and homologous recombination (HR). In this review, we focused on the engagement of proteins in the DNA damage response (DDR) modulated by phosphorylation and ubiquitylation, including ATM, DNA-PKcs, CtIP, MDM2, and ubiquitin ligases. The involvement and function of acetylation, methylation, PARylation, and their essential proteins were also investigated, providing a repository of candidate targets for DDR regulators. However, there is a lack of radioprotectors in spite of their consideration in the discovery of radiosensitizers. We proposed new perspectives for the research and development of future agents against space radiation by the systematic integration and utilization of evolutionary strategies, including multi-omics analyses, rational computing methods, drug repositioning, and combinations of drugs and targets, which may facilitate the use of radioprotectors in practical applications in human space exploration to combat fatal radiation hazards. Full article

(This article belongs to the Special Issue Cellular and Molecular Signaling Meet the Space Environment 2.0)

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19 pages, 1362 KB

Open AccessReview

The Interface between Cell Signaling Pathways and Pregnane X Receptor

by Robert S. Rogers, Annemarie Parker, Phill D. Vainer, Elijah Elliott, Dakota Sudbeck, Kaushal Parimi, Venkata P. Peddada, Parker G. Howe, Nick D’Ambrosio, Gregory Ruddy, Kaitlin Stackable, Megan Carney, Lauren Martin, Thomas Osterholt and Jeff L. Staudinger

Cells 2021, 10(11), 3262; https://doi.org/10.3390/cells10113262 - 22 Nov 2021

Cited by 13 | Viewed by 6786

Abstract

Highly expressed in the enterohepatic system, pregnane X receptor (PXR, NR1I2) is a well-characterized nuclear receptor (NR) that regulates the expression of genes in the liver and intestines that encode key drug metabolizing enzymes and drug transporter proteins in mammals. The net effect of PXR activation is to increase metabolism and clear drugs and xenobiotics from the body, producing a protective effect and mediating clinically significant drug interaction in patients on combination therapy. The complete understanding of PXR biology is thus important for the development of safe and effective therapeutic strategies. Furthermore, PXR activation is now known to specifically transrepress the inflammatory- and nutrient-signaling pathways of gene expression, thereby providing a mechanism for linking these signaling pathways together with enzymatic drug biotransformation pathways in the liver and intestines. Recent research efforts highlight numerous post-translational modifications (PTMs) which significantly influence the biological function of PXR. However, this thrust of research is still in its infancy. In the context of gene-environment interactions, we present a review of the recent literature that implicates PXR PTMs in regulating its clinically relevant biology. We also provide a discussion of how these PTMs likely interface with each other to respond to extracellular cues to appropriately modify PXR activity. Full article

(This article belongs to the Collection Current Trends in Xenobiotic Sensing Nuclear Receptor Research—The Many Facets of PXR and CAR)

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11 pages, 1808 KB

Open AccessArticle

Genetically Encoded Fluorescent Sensor for Poly-ADP-Ribose

by Ekaterina O. Serebrovskaya, Nadezda M. Podvalnaya, Varvara V. Dudenkova, Anna S. Efremova, Nadya G. Gurskaya, Dmitry A. Gorbachev, Artem V. Luzhin, Omar L. Kantidze, Elena V. Zagaynova, Stanislav I. Shram and Konstantin A. Lukyanov

Int. J. Mol. Sci. 2020, 21(14), 5004; https://doi.org/10.3390/ijms21145004 - 15 Jul 2020

Cited by 10 | Viewed by 4428

Abstract

Poly-(ADP-ribosyl)-ation (PARylation) is a reversible post-translational modification of proteins and DNA that plays an important role in various cellular processes such as DNA damage response, replication, transcription, and cell death. Here we designed a fully genetically encoded fluorescent sensor for poly-(ADP-ribose) (PAR) based on Förster resonance energy transfer (FRET). The WWE domain, which recognizes iso-ADP-ribose internal PAR-specific structural unit, was used as a PAR-targeting module. The sensor consisted of cyan Turquoise2 and yellow Venus fluorescent proteins, each in fusion with the WWE domain of RNF146 E3 ubiquitin ligase protein. This bipartite sensor named sPARroW (sensor for PAR relying on WWE) enabled monitoring of PAR accumulation and depletion in live mammalian cells in response to different stimuli, namely hydrogen peroxide treatment, UV irradiation and hyperthermia. Full article

(This article belongs to the Special Issue Imaging with Fluorescent Proteins)

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15 pages, 1873 KB

Open AccessFeature PaperReview

Emerging Roles of Post-Translational Modifications in Nucleotide Excision Repair

by Barbara N. Borsos, Hajnalka Majoros and Tibor Pankotai

Cells 2020, 9(6), 1466; https://doi.org/10.3390/cells9061466 - 15 Jun 2020

Cited by 13 | Viewed by 5577

Abstract

Nucleotide excision repair (NER) is a versatile DNA repair pathway which can be activated in response to a broad spectrum of UV-induced DNA damage, such as bulky adducts, including cyclobutane-pyrimidine dimers (CPDs) and 6–4 photoproducts (6–4PPs). Based on the genomic position of the lesion, two sub-pathways can be defined: (I) global genomic NER (GG-NER), involved in the ablation of damage throughout the whole genome regardless of the transcription activity of the damaged DNA locus, and (II) transcription-coupled NER (TC-NER), activated at DNA regions where RNAPII-mediated transcription takes place. These processes are tightly regulated by coordinated mechanisms, including post-translational modifications (PTMs). The fine-tuning modulation of the balance between the proteins, responsible for PTMs, is essential to maintain genome integrity and to prevent tumorigenesis. In this review, apart from the other substantial PTMs (SUMOylation, PARylation) related to NER, we principally focus on reversible ubiquitylation, which involves E3 ubiquitin ligase and deubiquitylase (DUB) enzymes responsible for the spatiotemporally precise regulation of NER. Full article

(This article belongs to the Special Issue Molecular Role of PARP in Health and Disease 2020)

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