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Cell Oct 2023ADP-ribosylation is a ubiquitous modification of biomolecules, including proteins and nucleic acids, that regulates various cellular functions in all kingdoms of life.... (Review)
Review
ADP-ribosylation is a ubiquitous modification of biomolecules, including proteins and nucleic acids, that regulates various cellular functions in all kingdoms of life. The recent emergence of new technologies to study ADP-ribosylation has reshaped our understanding of the molecular mechanisms that govern the establishment, removal, and recognition of this modification, as well as its impact on cellular and organismal function. These advances have also revealed the intricate involvement of ADP-ribosylation in human physiology and pathology and the enormous potential that their manipulation holds for therapy. In this review, we present the state-of-the-art findings covering the work in structural biology, biochemistry, cell biology, and clinical aspects of ADP-ribosylation.
Topics: Humans; ADP-Ribosylation; Proteins; DNA; RNA; Animals; Signal Transduction; Protein Processing, Post-Translational; ADP Ribose Transferases; Poly (ADP-Ribose) Polymerase-1
PubMed: 37832523
DOI: 10.1016/j.cell.2023.08.030 -
Proceedings of the National Academy of... Dec 2023PARP7 was reported to promote tumor growth in a cell-autonomous manner and by repressing the antitumor immune response. Nevertheless, the molecular mechanism of how...
PARP7 was reported to promote tumor growth in a cell-autonomous manner and by repressing the antitumor immune response. Nevertheless, the molecular mechanism of how PARP7-mediated ADP-ribosylation exerts these effects in cancer cells remains elusive. Here, we identified PARP7 as a nuclear and cysteine-specific mono-ADP-ribosyltransferase that modifies targets critical for regulating transcription, including the AP-1 transcription factor FRA1. Loss of FRA1 ADP-ribosylation via PARP7 inhibition by RBN-2397 or mutation of the ADP-ribosylation site C97 increased FRA1 degradation by the proteasome via PSMC3. The reduction in FRA1 protein levels promoted IRF1- and IRF3-dependent cytokine as well as proapoptotic gene expression, culminating in CASP8-mediated apoptosis. Furthermore, high PARP7 expression was indicative of the PARP7 inhibitor response in FRA1-positive lung and breast cancer cells. Collectively, our findings highlight the connected roles of PARP7 and FRA1 and emphasize the clinical potential of PARP7 inhibitors for FRA1-driven cancers.
Topics: Humans; ADP Ribose Transferases; ADP-Ribosylation; Apoptosis; Cell Transformation, Neoplastic; Gene Expression Regulation; Interferon Regulatory Factor-1; Interferon Regulatory Factor-3; Neoplasms; Nucleoside Transport Proteins; Proto-Oncogene Proteins c-fos
PubMed: 38011562
DOI: 10.1073/pnas.2309047120 -
Signal Transduction and Targeted Therapy Dec 2023Ferroptosis, a unique modality of cell death with mechanistic and morphological differences from other cell death modes, plays a pivotal role in regulating tumorigenesis... (Review)
Review
Ferroptosis, a unique modality of cell death with mechanistic and morphological differences from other cell death modes, plays a pivotal role in regulating tumorigenesis and offers a new opportunity for modulating anticancer drug resistance. Aberrant epigenetic modifications and posttranslational modifications (PTMs) promote anticancer drug resistance, cancer progression, and metastasis. Accumulating studies indicate that epigenetic modifications can transcriptionally and translationally determine cancer cell vulnerability to ferroptosis and that ferroptosis functions as a driver in nervous system diseases (NSDs), cardiovascular diseases (CVDs), liver diseases, lung diseases, and kidney diseases. In this review, we first summarize the core molecular mechanisms of ferroptosis. Then, the roles of epigenetic processes, including histone PTMs, DNA methylation, and noncoding RNA regulation and PTMs, such as phosphorylation, ubiquitination, SUMOylation, acetylation, methylation, and ADP-ribosylation, are concisely discussed. The roles of epigenetic modifications and PTMs in ferroptosis regulation in the genesis of diseases, including cancers, NSD, CVDs, liver diseases, lung diseases, and kidney diseases, as well as the application of epigenetic and PTM modulators in the therapy of these diseases, are then discussed in detail. Elucidating the mechanisms of ferroptosis regulation mediated by epigenetic modifications and PTMs in cancer and other diseases will facilitate the development of promising combination therapeutic regimens containing epigenetic or PTM-targeting agents and ferroptosis inducers that can be used to overcome chemotherapeutic resistance in cancer and could be used to prevent other diseases. In addition, these mechanisms highlight potential therapeutic approaches to overcome chemoresistance in cancer or halt the genesis of other diseases.
Topics: Humans; Ferroptosis; Protein Processing, Post-Translational; Neoplasms; DNA Methylation; Epigenesis, Genetic; Antineoplastic Agents; Kidney Diseases; Lung Diseases
PubMed: 38072908
DOI: 10.1038/s41392-023-01720-0 -
Molecular Cell Jul 2023Oncogenic mutations in isocitrate dehydrogenases 1 and 2 (IDH1/2) produce 2-hydroxyglutarate (2HG), which inhibits dioxygenases that modulate chromatin dynamics. The...
Oncogenic mutations in isocitrate dehydrogenases 1 and 2 (IDH1/2) produce 2-hydroxyglutarate (2HG), which inhibits dioxygenases that modulate chromatin dynamics. The effects of 2HG have been reported to sensitize IDH tumors to poly-(ADP-ribose) polymerase (PARP) inhibitors. However, unlike PARP-inhibitor-sensitive BRCA1/2 tumors, which exhibit impaired homologous recombination, IDH-mutant tumors have a silent mutational profile and lack signatures associated with impaired homologous recombination. Instead, 2HG-producing IDH mutations lead to a heterochromatin-dependent slowing of DNA replication accompanied by increased replication stress and DNA double-strand breaks. This replicative stress manifests as replication fork slowing, but the breaks are repaired without a significant increase in mutation burden. Faithful resolution of replicative stress in IDH-mutant cells is dependent on poly-(ADP-ribosylation). Treatment with PARP inhibitors increases DNA replication but results in incomplete DNA repair. These findings demonstrate a role for PARP in the replication of heterochromatin and further validate PARP as a therapeutic target in IDH-mutant tumors.
Topics: Humans; BRCA1 Protein; Heterochromatin; Poly(ADP-ribose) Polymerase Inhibitors; BRCA2 Protein; Homologous Recombination; Neoplasms; Mutation; Isocitrate Dehydrogenase
PubMed: 37311462
DOI: 10.1016/j.molcel.2023.05.026 -
Cell Reports Oct 2023Lipid droplets (LDs) play a crucial role in maintaining cellular lipid balance by storing and delivering lipids as needed. However, the intricate lipolytic pathways...
Lipid droplets (LDs) play a crucial role in maintaining cellular lipid balance by storing and delivering lipids as needed. However, the intricate lipolytic pathways involved in LD turnover remain poorly described, hindering our comprehension of lipid catabolism and related disorders. Here, we show a function of the small GTPase ARL8B in mediating LD turnover in lysosomes. ARL8B-GDP localizes to LDs, while ARL8-GTP predominantly favors lysosomes. GDP binding induces a conformation with an exposed N-terminal amphipathic helix, enabling ARL8B to bind to LDs. By associating with LDs and lysosomes, and with its property to form a heterotypic complex, ARL8B mediates LD-lysosome contacts and efficient lipid transfer between these organelles. In human macrophages, this ARL8B-dependent LD turnover mechanism appears as the major lipolytic pathway. Our finding opens exciting possibilities for understanding the molecular mechanisms underlying LD degradation and its potential implications for inflammatory disorders.
Topics: Humans; Lipid Droplets; Monomeric GTP-Binding Proteins; Signal Transduction; Lysosomes; Lipids; Lipid Metabolism; ADP-Ribosylation Factors
PubMed: 37777960
DOI: 10.1016/j.celrep.2023.113203 -
The Journal of Biological Chemistry Nov 2023O-linked N-acetylglucosamine (O-GlcNAc) glycosylation, a prevalent protein post-translational modification (PTM) that occurs intracellularly, has been shown to crosstalk...
O-linked N-acetylglucosamine (O-GlcNAc) glycosylation, a prevalent protein post-translational modification (PTM) that occurs intracellularly, has been shown to crosstalk with phosphorylation and ubiquitination. However, it is unclear whether it interplays with other PTMs. Here we studied its relationship with ADP-ribosylation, which involves decorating target proteins with the ADP-ribose moiety. We discovered that the poly(ADP-ribosyl)ation "eraser", ADP-ribose glycohydrolase (PARG), is O-GlcNAcylated at Ser26, which is in close proximity to its nuclear localization signal. O-GlcNAcylation of PARG promotes nuclear localization and chromatin association. Upon DNA damage, O-GlcNAcylation augments the recruitment of PARG to DNA damage sites and interacting with proliferating cell nuclear antigen (PCNA). In hepatocellular carcinoma (HCC) cells, PARG O-GlcNAcylation enhances the poly(ADP-ribosyl)ation of DNA damage-binding protein 1 (DDB1) and attenuates its auto-ubiquitination, thereby stabilizing DDB1 and allowing it to degrade its downstream targets, such as c-Myc. We further demonstrated that PARG-S26A, the O-GlcNAc-deficient mutant, promoted HCC in mouse xenograft models. Our findings thus reveal that PARG O-GlcNAcylation inhibits HCC, and we propose that O-GlcNAc glycosylation may crosstalk with many other PTMs.
Topics: Animals; Humans; Mice; Acetylglucosamine; ADP-Ribosylation; Carcinoma, Hepatocellular; Glycoside Hydrolases; Liver Neoplasms; Poly Adenosine Diphosphate Ribose; Glycosylation; Protein Processing, Post-Translational
PubMed: 37858678
DOI: 10.1016/j.jbc.2023.105354 -
Journal of Molecular Cell Biology Nov 2023Legionella pneumophila is a Gram-negative bacterium ubiquitously present in freshwater environments and causes a serious type of pneumonia called Legionnaires' disease.... (Review)
Review
Legionella pneumophila is a Gram-negative bacterium ubiquitously present in freshwater environments and causes a serious type of pneumonia called Legionnaires' disease. During infections, L. pneumophila releases over 300 effector proteins into host cells through an Icm/Dot type IV secretion system to manipulate the host defense system for survival within the host. Notably, certain effector proteins mediate posttranslational modifications (PTMs), serving as useful approaches exploited by L. pneumophila to modify host proteins. Some effectors catalyze the addition of host protein PTMs, while others mediate the removal of PTMs from host proteins. In this review, we summarize L. pneumophila effector-mediated PTMs of host proteins, including phosphorylation, ubiquitination, glycosylation, AMPylation, phosphocholination, methylation, and ADP-ribosylation, as well as dephosphorylation, deubiquitination, deAMPylation, deADP-ribosylation, dephosphocholination, and delipidation. We describe their molecular mechanisms and biological functions in the regulation of bacterial growth and Legionella-containing vacuole biosynthesis and in the disruption of host immune and defense machinery.
Topics: Humans; Legionella pneumophila; Legionnaires' Disease; Protein Processing, Post-Translational; Vacuoles; Ubiquitination
PubMed: 37156500
DOI: 10.1093/jmcb/mjad032 -
Pathogens (Basel, Switzerland) Jul 2023Aberrant adenosine diphosphate-ribose (ADP)-ribosylation of proteins and nucleic acids is associated with multiple disease processes such as infections and chronic... (Review)
Review
Aberrant adenosine diphosphate-ribose (ADP)-ribosylation of proteins and nucleic acids is associated with multiple disease processes such as infections and chronic inflammatory diseases. The poly(ADP-ribose) polymerase (PARP)/ADP-ribosyltransferase (ART) family members promote mono- or poly-ADP-ribosylation. Although evidence has linked PARPs/ARTs and macrophages in the context of chronic inflammation, the underlying mechanisms remain incompletely understood. This review provides an overview of literature focusing on the roles of PARP1/ARTD1, PARP7/ARTD14, PARP9/ARTD9, and PARP14/ARTD8 in macrophages. PARPs/ARTs regulate changes in macrophages during chronic inflammatory processes not only via catalytic modifications but also via non-catalytic mechanisms. Untangling complex mechanisms, by which PARPs/ARTs modulate macrophage phenotype, and providing molecular bases for the development of new therapeutics require the development and implementation of innovative technologies.
PubMed: 37513811
DOI: 10.3390/pathogens12070964 -
Nature Aug 2023The mechanisms by which viruses hijack the genetic machinery of the cells they infect are of current interest. When bacteriophage T4 infects Escherichia coli, it uses...
The mechanisms by which viruses hijack the genetic machinery of the cells they infect are of current interest. When bacteriophage T4 infects Escherichia coli, it uses three different adenosine diphosphate (ADP)-ribosyltransferases (ARTs) to reprogram the transcriptional and translational apparatus of the host by ADP-ribosylation using nicotinamide adenine dinucleotide (NAD) as a substrate. NAD has previously been identified as a 5' modification of cellular RNAs. Here we report that the T4 ART ModB accepts not only NAD but also NAD-capped RNA (NAD-RNA) as a substrate and attaches entire RNA chains to acceptor proteins in an 'RNAylation' reaction. ModB specifically RNAylates the ribosomal proteins rS1 and rL2 at defined Arg residues, and selected E. coli and T4 phage RNAs are linked to rS1 in vivo. T4 phages that express an inactive mutant of ModB have a decreased burst size and slowed lysis of E. coli. Our findings reveal a distinct biological role for NAD-RNA, namely the activation of the RNA for enzymatic transfer to proteins. The attachment of specific RNAs to ribosomal proteins might provide a strategy for the phage to modulate the host's translation machinery. This work reveals a direct connection between RNA modification and post-translational protein modification. ARTs have important roles far beyond viral infections, so RNAylation may have far-reaching implications.
Topics: ADP Ribose Transferases; Bacteriophage T4; Escherichia coli; NAD; Ribosomal Proteins; Viral Proteins; Escherichia coli Proteins; RNA; Protein Biosynthesis; Gene Expression Regulation, Bacterial; Protein Processing, Post-Translational
PubMed: 37587340
DOI: 10.1038/s41586-023-06429-2 -
Frontiers in Endocrinology 2024
Topics: Histones; Chromatin; Epigenesis, Genetic
PubMed: 38405145
DOI: 10.3389/fendo.2024.1373368