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ADP-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control.

ABSTRACT: Among the post-translational modifications of proteins, ADP-ribosylation has been studied for over fifty years, and a large set of functions, including DNA repair, transcription, and cell signaling, have been assigned to this post-translational modification (PTM). This review presents an update on the function of a large set of enzyme writers, the readers that are recruited by the modified targets, and the erasers that reverse the modification to the original amino acid residue, removing the covalent bonds formed. In particular, the review provides details on the involvement of the enzymes performing monoADP-ribosylation/polyADP-ribosylation (MAR/PAR) cycling in cancers. Of note, there is potential for the application of the inhibitors developed for cancer also in the therapy of non-oncological diseases such as the protection against oxidative stress, the suppression of inflammatory responses, and the treatment of neurodegenerative diseases. This field of studies is not concluded, since novel enzymes are being discovered at a rapid pace.

SUBMITTER: Poltronieri P

PROVIDER: S-EPMC8509805 | biostudies-literature |

REPOSITORIES: biostudies-literature

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ADP-Ribosylation Post-Translational Modification: An Overview with a Focus on RNA Biology and New Pharmacological Perspectives.

Project description:Cellular functions are regulated through the gene expression program by the transcription of new messenger RNAs (mRNAs), alternative RNA splicing, and protein synthesis. To this end, the post-translational modifications (PTMs) of proteins add another layer of complexity, creating a continuously fine-tuned regulatory network. ADP-ribosylation (ADPr) is an ancient reversible modification of cellular macromolecules, regulating a multitude of key functional processes as diverse as DNA damage repair (DDR), transcriptional regulation, intracellular transport, immune and stress responses, and cell survival. Additionally, due to the emerging role of ADP-ribosylation in pathological processes, ADP-ribosyltransferases (ARTs), the enzymes involved in ADPr, are attracting growing interest as new drug targets. In this review, an overview of human ARTs and their related biological functions is provided, mainly focusing on the regulation of ADP-ribosyltransferase Diphtheria toxin-like enzymes (ARTD)-dependent RNA functions. Finally, in order to unravel novel gene functional relationships, we propose the analysis of an inventory of human gene clusters, including ARTDs, which share conserved sequences at 3' untranslated regions (UTRs).

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Characterization of an <i>Aedes</i> ADP-Ribosylation Protein Domain and Role of Post-Translational Modification during Chikungunya Virus Infection.

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Genetic regulation of post-translational modification of two distinct proteins.

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Post-translational modification control of RNA-binding protein hnRNPK function.

Project description:Heterogeneous nuclear ribonucleoprotein K (hnRNPK), a ubiquitously occurring RNA-binding protein (RBP), can interact with numerous nucleic acids and various proteins and is involved in a number of cellular functions including transcription, translation, splicing, chromatin remodelling, etc. Through its abundant biological functions, hnRNPK has been implicated in cellular events including proliferation, differentiation, apoptosis, DNA damage repair and the stress and immune responses. Thus, it is critical to understand the mechanism of hnRNPK regulation and its downstream effects on cancer and other diseases. A number of recent studies have highlighted that several post-translational modifications (PTMs) possibly play an important role in modulating hnRNPK function. Phosphorylation is the most widely occurring PTM in hnRNPK. For example, in vivo analyses of sites such as S116 and S284 illustrate the purpose of PTM of hnRNPK in altering its subcellular localization and its ability to bind target nucleic acids or proteins. Other PTMs such as methylation, ubiquitination, sumoylation, glycosylation and proteolytic cleavage are increasingly implicated in the regulation of DNA repair, cellular stresses and tumour growth. In this review, we describe the PTMs that impact upon hnRNPK function on gene expression programmes and different disease states. This knowledge is key in allowing us to better understand the mechanism of hnRNPK regulation.

| S-EPMC6451366 | biostudies-literature

Post-translational modification of the major human surfactant-associated proteins.

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Post-translational modification of OCT4 in breast cancer tumorigenesis.

Project description:Recurrence and drug resistance of breast cancer are still the main reasons for breast cancer-associated deaths. Cancer stem cell (CSC) model has been proposed as a hypothesis for the lethality of breast cancer. Molecular mechanisms underlying CSC maintenance are still unclear. In this study, we generated mammospheres derived from breast cancer MDA-MB231 cells and MCF7 cells to enrich CSCs and performed DNA microarray analysis. We found that the expression of carboxy terminus of HSP70-interacting protein (CHIP) E3 ubiquitin ligase was significantly downregulated in breast CSCs. CHIP depletion increased mammosphere formation, whereas CHIP overexpression reversed this effect. We identified interactomes by mass spectrometry and detected CHIP directly interacted with OCT4, a stemness factor. CHIP overexpression decreased OCT4 stability through proteasomal degradation. CHIP induced OCT4 ubiquitination, whereas H260Q, a catalytic CHIP mutant, did not. Interestingly, we determined that OCT4 was ubiquitinated at lysine 284, and CHIP overexpression did not degrade K284R mutant OCT4. CHIP overexpression decreased the proliferation and side population of breast cancer cells, but these were not occurred in K284R mutant OCT4 overexpressed cells. Only 1000 cells showing CHIP depletion or OCT4 overexpression sufficiently generated breast tumors and lung metastases in xenografted mice. Ubiquitination-defective mutant of OCT4(K284R) overexpressed cells drastically generated tumor burdens in mice. Patients with breast cancer who showed low CHIP expression had poor survival probability. Taken together, we suggest that CHIP-induced OCT4 ubiquitination is important in breast CSCs. Regulation of CHIP expression and OCT4 protein stability is a considerable approach for breast cancer therapy.

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A family of macrodomain proteins reverses cellular mono-ADP-ribosylation.

Project description:ADP-ribosylation is a reversible post-translational modification with wide-ranging biological functions in all kingdoms of life. A variety of enzymes use NAD(+) to transfer either single or multiple ADP-ribose (ADPr) moieties onto distinct amino acid substrates, often in response to DNA damage or other stresses. Poly-ADPr-glycohydrolase readily reverses poly-ADP-ribosylation induced by the DNA-damage sensor PARP1 and other enzymes, but it does not remove the most proximal ADPr linked to the target amino acid. Searches for enzymes capable of fully reversing cellular mono-ADP-ribosylation back to the unmodified state have proved elusive, which leaves a gap in the understanding of this modification. Here, we identify a family of macrodomain enzymes present in viruses, yeast and animals that reverse cellular ADP-ribosylation by acting on mono-ADP-ribosylated substrates. Our discoveries establish the complete reversibility of PARP-catalyzed cellular ADP-ribosylation as a regulatory modification.

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