Unleashing viral mimicry: A combinatorial strategy to enhance the efficacy of PARP7 inhibitors.

Cancer cells exploit mechanisms to evade immune detection triggered by aberrant self-nucleic acids (NA). PARP7, a key player in this immune evasion strategy, has emerged as a potential target for cancer therapy. PARP7 inhibitors reactivate NA sensing, resulting in type I interferon (IFN) signaling, programmed cell death, anti-tumor immunity, and tumor regression.

Expanding the Perspective on PARP1 and Its Inhibitors in Cancer Therapy: From DNA Damage Repair to Immunomodulation.

The emergence of PARP inhibitors as a therapeutic strategy for tumors with high genomic instability, particularly those harboring BRCA mutations, has advanced cancer treatment. However, recent advances have illuminated a multifaceted role of PARP1 beyond its canonical function in DNA damage repair. This review explores the expanding roles of PARP1, highlighting its crucial interplay with the immune system during tumorigenesis.

PRAMEL7 and CUL2 decrease NuRD stability to establish ground-state pluripotency.

Pluripotency is established in E4.5 preimplantation epiblast. Embryonic stem cells (ESCs) represent the immortalization of pluripotency, however, their gene expression signature only partially resembles that of developmental ground-state.

Covalent PARylation of DNA base excision repair proteins regulates DNA demethylation.

The intracellular ATP-ribosyltransferases PARP1 and PARP2, contribute to DNA base excision repair (BER) and DNA demethylation and have been implicated in epigenetic programming in early mammalian development. Recently, proteomic analyses identified BER proteins to be covalently poly-ADP-ribosylated by PARPs. The role of this posttranslational modification in the BER process is unknown.

PARP7-mediated ADP-ribosylation of FRA1 promotes cancer cell growth by repressing IRF1- and IRF3-dependent apoptosis.

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.

Combinatorial Treatment with PARP and MAPK Inhibitors Overcomes Phenotype Switch-Driven Drug Resistance in Advanced Melanoma.

Unlabelled: Metastatic melanoma is either intrinsically resistant or rapidly acquires resistance to targeted therapy treatments, such as MAPK inhibitors (MAPKi). A leading cause of resistance to targeted therapy is a dynamic transition of melanoma cells from a proliferative to a highly invasive state, a phenomenon called phenotype switching. Mechanisms regulating phenotype switching represent potential targets for improving treatment of patients with melanoma.

Poly(ADP-Ribose) Polymerase-1 Lacking Enzymatic Activity Is Not Compatible with Mouse Development.

Poly(ADP-ribose) polymerase-1 (PARP1) binds DNA lesions to catalyse poly(ADP-ribosyl)ation (PARylation) using NAD+ as a substrate. PARP1 plays multiple roles in cellular activities, including DNA repair, transcription, cell death, and chromatin remodelling. However, whether these functions are governed by the enzymatic activity or scaffolding function of PARP1 remains elusive.

Absence of mitochondrial SLC25A51 enhances PARP1-dependent DNA repair by increasing nuclear NAD+ levels.

Though the effect of the recently identified mitochondrial NAD+ transporter SLC25A51 on glucose metabolism has been described, its contribution to other NAD+-dependent processes throughout the cell such as ADP-ribosylation remains elusive. Here, we report that absence of SLC25A51 leads to increased NAD+ concentration not only in the cytoplasm and but also in the nucleus. The increase is not associated with upregulation of the salvage pathway, implying an accumulation of constitutively synthesized NAD+ in the cytoplasm and nucleus.

Altered cytoplasmic and nuclear ADP-ribosylation levels analyzed with an improved ADP-ribose binder are a prognostic factor in renal cell carcinoma.

ADP-ribosylation (ADPR) of proteins is catalyzed by ADP-ribosyltransferases, which are targeted by inhibitors (i.e. poly(ADP-ribose) polymerase inhibitors [PARPi]).

Subcellular Quantitation of ADP-Ribosylation by High-Content Microscopy.

ADP-ribosylation is a posttranslational modification with many functions ranging from the DNA damage response to transcriptional regulation. While nuclear ADP-ribosylation has been extensively studied in the context of genotoxic stress mediated by PARP1, signaling by other members of the family and in other cellular compartments is still not as well understood. In recent years, however, progress has been made with the development of new tools for detection of ADP-ribosylation by immunofluorescence, which allows for a spatial differentiation of signal intensity for different cellular compartments.

Tankyrase-mediated ADP-ribosylation is a regulator of TNF-induced death.

Tumor necrosis factor (TNF) is a key component of the innate immune response. Upon binding to its receptor, TNFR1, it promotes production of other cytokines via a membrane-bound complex 1 or induces cell death via a cytosolic complex 2. To understand how TNF-induced cell death is regulated, we performed mass spectrometry of complex 2 and identified tankyrase-1 as a native component that, upon a death stimulus, mediates complex 2 poly-ADP-ribosylation (PARylation).

Interplay between ADP-ribosyltransferases and essential cell signaling pathways controls cellular responses.

Signaling cascades provide integrative and interactive frameworks that allow the cell to respond to signals from its environment and/or from within the cell itself. The dynamic regulation of mammalian cell signaling pathways is often modulated by cascades of protein post-translational modifications (PTMs). ADP-ribosylation is a PTM that is catalyzed by ADP-ribosyltransferases and manifests as mono- (MARylation) or poly- (PARylation) ADP-ribosylation depending on the addition of one or multiple ADP-ribose units to protein substrates.

A Novel Spectral Annotation Strategy Streamlines Reporting of Mono-ADP-ribosylated Peptides Derived from Mouse Liver and Spleen in Response to IFN-γ.

Mass-spectrometry-enabled ADP-ribosylation workflows are developing rapidly, providing researchers a variety of ADP-ribosylome enrichment strategies and mass spectrometric acquisition options. Despite the growth spurt in upstream technologies, systematic ADP-ribosyl (ADPr) peptide mass spectral annotation methods are lacking. HCD-dependent ADP-ribosylome studies are common, but the resulting MS2 spectra are complex, owing to a mixture of b/y-ions and the m/p-ion peaks representing one or more dissociation events of the ADPr moiety (m-ion) and peptide (p-ion).

Identification of the Mouse T Cell ADP-Ribosylome Uncovers ARTC2.2 Mediated Regulation of CD73 by ADP-Ribosylation.

Mouse T cells express the ecto-ADP-ribosyltransferase ARTC2.2, which can transfer the ADP-ribose group of extracellular nicotinamide adenine dinucleotide (NAD) to arginine residues of various cell surface proteins thereby influencing their function. Several targets of ARTC2.

ADP-ribosyltransferases, an update on function and nomenclature.

ADP-ribosylation, a modification of proteins, nucleic acids, and metabolites, confers broad functions, including roles in stress responses elicited, for example, by DNA damage and viral infection and is involved in intra- and extracellular signaling, chromatin and transcriptional regulation, protein biosynthesis, and cell death. ADP-ribosylation is catalyzed by ADP-ribosyltransferases (ARTs), which transfer ADP-ribose from NAD onto substrates. The modification, which occurs as mono- or poly-ADP-ribosylation, is reversible due to the action of different ADP-ribosylhydrolases.

Investigation of Mitochondrial ADP-Ribosylation Via Immunofluorescence.

ADP-ribosylation is a posttranslational protein modification, involved in various cellular processes, ranging from DNA-damage repair to apoptosis. While its function has been studied amply with respect to genotoxic stress-associated nuclear ADP-ribosylation, the functional relevance of mitochondrial ADP-ribosylation remains so far poorly studied. This is mainly attributed to the absence of powerful techniques able to detect the modification.

Establishment of a Mass-Spectrometry-Based Method for the Identification of the Whole Blood and Plasma ADP-Ribosylomes.

Blood and plasma proteins are heavily investigated as biomarkers for different diseases. However, the post-translational modification states of these proteins are rarely analyzed since blood contains many enzymes that rapidly remove these modifications after sampling. In contrast to the well-described role of protein ADP-ribosylation in cells and organs, its role in blood remains mostly uncharacterized.

MyoD induces ARTD1 and nucleoplasmic poly-ADP-ribosylation during fibroblast to myoblast transdifferentiation.

While protein ADP-ribosylation was reported to regulate differentiation and dedifferentiation, it has so far not been studied during transdifferentiation. Here, we found that MyoD-induced transdifferentiation of fibroblasts to myoblasts promotes the expression of the ADP-ribosyltransferase . Comprehensive analysis of the genome architecture by Hi-C and RNA-seq analysis during transdifferentiation indicated that ARTD1 locally contributed to A/B compartmentalization and coregulated a subset of MyoD target genes that were however not sufficient to alter transdifferentiation.

Uncovering the Invisible: Mono-ADP-ribosylation Moved into the Spotlight.

Adenosine diphosphate (ADP)-ribosylation is a nicotinamide adenine dinucleotide (NAD)-dependent post-translational modification that is found on proteins as well as on nucleic acids. While ARTD1/PARP1-mediated poly-ADP-ribosylation has extensively been studied in the past 60 years, comparably little is known about the physiological function of mono-ADP-ribosylation and the enzymes involved in its turnover. Promising technological advances have enabled the development of innovative tools to detect NAD and NAD/NADH (H for hydrogen) ratios as well as ADP-ribosylation.

Cytoplasmic ADP-ribosylation levels correlate with markers of patient outcome in distinct human cancers.

ADP-ribosylation (ADPR) is a posttranslational modification whose importance in oncology keeps increasing due to frequent use of PARP inhibitors (PARPi) to treat different tumor types. Due to the lack of suitable tools to analyze cellular ADPR levels, ADPR's significance for cancer progression and patient outcome is unclear. In this study, we assessed ADPR levels by immunohistochemistry using a newly developed anti-ADP-ribose (ADPr) antibody, which is able to detect both mono- and poly-ADPR.

New insight into the significance of KLF4 PARylation in genome stability, carcinogenesis, and therapy.

KLF4 plays a critical role in determining cell fate responding to various stresses or oncogenic signaling. Here, we demonstrated that KLF4 is tightly regulated by poly(ADP-ribosyl)ation (PARylation). We revealed the subcellular compartmentation for KLF4 is orchestrated by PARP1-mediated PARylation.

Tumor cell endogenous HIF-1α activity induces aberrant angiogenesis and interacts with TRAF6 pathway required for colorectal cancer development.

Hypoxia and inflammation are key factors for colorectal cancer tumorigenesis. The colonic epithelium belongs to the tissues with the lowest partial pressure of oxygen in the body, and chronic inflammation is associated with an increased chance to develop colon cancer. How the colonic epithelium responds to hypoxia and inflammation during tumorigenesis remains to be elucidated.

Gas-Phase Fragmentation of ADP-Ribosylated Peptides: Arginine-Specific Side-Chain Losses and Their Implication in Database Searches.

ADP-ribosylation is a reversible post-translational modification of proteins that has been linked to many biological processes. The identification of ADP-ribosylated proteins and particularly of their acceptor amino acids remains a major challenge. The attachment sites of the modification are difficult to localize by mass spectrometry (MS) because of the labile nature of the linkage and the complex fragmentation pattern of the ADP-ribose in MS/MS experiments.