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Cells
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Protein Mono-ADP-Ribosylation in the Control of Cell Functions
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Protein Mono-ADP-Ribosylation in the Control of Cell Functions

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 44833

Special Issue Editors

Prof. Herwig Schüler

E-Mail Website
Guest Editor
Karolinska Institutet, Department of Biosciences and Nutrition, 14157 Huddinge, Sweden
Interests: ADP-ribosylating toxins; enzymatic mechanisms; enzyme inhibitors; PARP biochemistry; X-ray crystallography
Dr. Giovanna Grimaldi

E-Mail Website
Guest Editor
Institute of Biochemistry and Cell Biology, National Research Council, 80131 Naples, Italy
Interests: PARPs; mono-ADP-ribosylation; Golgi complex; intracellular transport; cell-cycle; apoptosis; stress response; post-translational modifications; cancer; signaling

Special Issue Information

Dear Colleagues,

Mono-ADP-ribosylation of proteins was discovered over 50 years ago, when it became clear that pathogenic bacteria express ADP-ribosylating toxins that inactivate host cell proteins. Later, it was found that higher eukaryotes possess homologs of one major clade of toxins, the Clostridium toxin-like ARTC enzymes, that have extracellular activities. Homologs of the second major clade of toxins, the diphtheria toxin-like ARTD enzymes—better known as PARPs (or poly-ADP-ribose- polymerases)—are instead represented in the cytosol and nuclei of eukaryotic cells, and are responsible for both poly- and mono-ADP-ribosylation of targets.

The study of mono-ADP-ribosylation, in particular, has been difficult owing to a lack of research tools as well as chemistry that is hard to detect by mass spectrometry and a transient nature that obstructs detection in cells and tissues. The new millennium and especially the past few years have brought a range of developments and discoveries that collectively represent a major advance for this research field. The definition of novel pathways driven by MARylation—from the RNA regulation to the control intracellular transport—along with the identification of specific inhibitors, will likely have an important impact on cell biology research, with potential applications for the treatment of diseases.

This Special Issue will give a timely view of the field of mono-ADP-ribosylation. Contributions by expert laboratories will present methods, tools, and functional advances. We hope that this collection of articles will be a useful summary for the mono-ADP-ribosylation experts as well as a helpful introduction for those colleagues who stumble upon the modification when studying other aspects of physiology and medicine.

Prof. Herwig Schüler
Dr. Giovanna Grimaldi
Guest Editors

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Keywords

  • mono-ADP-ribosylation
  • PARPs
  • ADP-ribosylating toxins
  • exo-mARTs
  • Intracellular signaling
  • oxidative stress
  • PARP inhibitors
  • mass-spectrometry
  • post-translational modifications

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Published Papers (8 papers)

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Research

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17 pages, 4564 KiB  
Article
Characterization of PARP6 Function in Knockout Mice and Patients with Developmental Delay
by Anke Vermehren-Schmaedick, Jeffrey Y. Huang, Madison Levinson, Matthew B. Pomaville, Sarah Reed, Gary A. Bellus, Fred Gilbert, Boris Keren, Delphine Heron, Damien Haye, Christine Janello, Christine Makowski, Katharina Danhauser, Lev M. Fedorov, Tobias B. Haack, Kevin M. Wright and Michael S. Cohen
Cells 2021, 10(6), 1289; https://doi.org/10.3390/cells10061289 - 22 May 2021
Cited by 8 | Viewed by 5074
Abstract
PARP6, a member of a family of enzymes (17 in humans) known as poly-ADP-ribose polymerases (PARPs), is a neuronally enriched PARP. While previous studies from our group show that Parp6 is a regulator of dendrite morphogenesis in rat hippocampal neurons, its function in [...] Read more.
PARP6, a member of a family of enzymes (17 in humans) known as poly-ADP-ribose polymerases (PARPs), is a neuronally enriched PARP. While previous studies from our group show that Parp6 is a regulator of dendrite morphogenesis in rat hippocampal neurons, its function in the nervous system in vivo is poorly understood. Here, we describe the generation of a Parp6 loss-of-function mouse model for examining the function of Parp6 during neurodevelopment in vivo. Using CRISPR-Cas9 mutagenesis, we generated a mouse line that expressed a Parp6 truncated variant (Parp6TR) in place of Parp6WT. Unlike Parp6WT, Parp6TR is devoid of catalytic activity. Homozygous Parp6TR do not exhibit obvious neuromorphological defects during development, but nevertheless die perinatally. This suggests that Parp6 catalytic activity is important for postnatal survival. We also report PARP6 mutations in six patients with several neurodevelopmental disorders, including microencephaly, intellectual disabilities, and epilepsy. The most severe mutation in PARP6 (C563R) results in the loss of catalytic activity. Expression of Parp6C563R in hippocampal neurons decreases dendrite morphogenesis. To gain further insight into PARP6 function in neurons we also performed a BioID proximity labeling experiment in hippocampal neurons and identified several microtubule-binding proteins (e.g., MAP-2) using proteomics. Taken together, our results suggest that PARP6 is an essential microtubule-regulatory gene in mice, and that the loss of PARP6 catalytic activity has detrimental effects on neuronal function in humans. Full article
(This article belongs to the Special Issue Protein Mono-ADP-Ribosylation in the Control of Cell Functions)
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11 pages, 1442 KiB  
Communication
PARP10 Multi-Site Auto- and Histone MARylation Visualized by Acid-Urea Gel Electrophoresis
by Antonio Ginés García-Saura and Herwig Schüler
Cells 2021, 10(3), 654; https://doi.org/10.3390/cells10030654 - 15 Mar 2021
Cited by 10 | Viewed by 3503
Abstract
Poly-ADP-ribose polymerase (PARP)-family ADP-ribosyltransferases function in various signaling pathways, predominantly in the nucleus and cytosol. Although PARP inhibitors are in clinical practice for cancer therapy, the enzymatic activities of individual PARP family members are yet insufficiently understood. We studied PARP10, a mono-ADP-ribosyltransferase and [...] Read more.
Poly-ADP-ribose polymerase (PARP)-family ADP-ribosyltransferases function in various signaling pathways, predominantly in the nucleus and cytosol. Although PARP inhibitors are in clinical practice for cancer therapy, the enzymatic activities of individual PARP family members are yet insufficiently understood. We studied PARP10, a mono-ADP-ribosyltransferase and potential drug target. Using acid-urea gel electrophoresis, we found that the isolated catalytic domain of PARP10 auto-ADP-ribosylates (MARylates) at eight or more acceptor residues. We isolated individual species with either singular or several modifications and then analyzed them by mass spectrometry. The results confirmed multi-site MARylation in a random order and identified four acceptor residues. The mutagenesis of singular acceptor residues had a minor impact on the overall auto-MARylation level and no effect on the MARylation of histone H3.1. Together, our results suggest that PARP10 automodification may have functions in the regulation of intramolecular or partner binding events, rather than of its enzymatic catalysis. This contributes to a better understanding of PARP10 functions, and, in the long run, to gauging the consequences of PARP inhibitor actions. Full article
(This article belongs to the Special Issue Protein Mono-ADP-Ribosylation in the Control of Cell Functions)
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19 pages, 3709 KiB  
Article
PARP7 and Mono-ADP-Ribosylation Negatively Regulate Estrogen Receptor α Signaling in Human Breast Cancer Cells
by Marit Rasmussen, Susanna Tan, Venkata S. Somisetty, David Hutin, Ninni Elise Olafsen, Anders Moen, Jan H. Anonsen, Denis M. Grant and Jason Matthews
Cells 2021, 10(3), 623; https://doi.org/10.3390/cells10030623 - 11 Mar 2021
Cited by 31 | Viewed by 6226
Abstract
ADP-ribosylation is a post-translational protein modification catalyzed by a family of proteins known as poly-ADP-ribose polymerases. PARP7 (TIPARP; ARTD14) is a mono-ADP-ribosyltransferase involved in several cellular processes, including responses to hypoxia, innate immunity and regulation of nuclear receptors. Since previous studies suggested that [...] Read more.
ADP-ribosylation is a post-translational protein modification catalyzed by a family of proteins known as poly-ADP-ribose polymerases. PARP7 (TIPARP; ARTD14) is a mono-ADP-ribosyltransferase involved in several cellular processes, including responses to hypoxia, innate immunity and regulation of nuclear receptors. Since previous studies suggested that PARP7 was regulated by 17β-estradiol, we investigated whether PARP7 regulates estrogen receptor α signaling. We confirmed the 17β-estradiol-dependent increases of PARP7 mRNA and protein levels in MCF-7 cells, and observed recruitment of estrogen receptor α to the promoter of PARP7. Overexpression of PARP7 decreased ligand-dependent estrogen receptor α signaling, while treatment of PARP7 knockout MCF-7 cells with 17β-estradiol resulted in increased expression of and recruitment to estrogen receptor α target genes, in addition to increased proliferation. Co-immunoprecipitation assays revealed that PARP7 mono-ADP-ribosylated estrogen receptor α, and mass spectrometry mapped the modified peptides to the receptor’s ligand-independent transactivation domain. Co-immunoprecipitation with truncated estrogen receptor α variants identified that the hinge region of the receptor is required for PARP7-dependent mono-ADP-ribosylation. These results imply that PARP7-mediated mono-ADP-ribosylation may play an important role in estrogen receptor positive breast cancer. Full article
(This article belongs to the Special Issue Protein Mono-ADP-Ribosylation in the Control of Cell Functions)
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24 pages, 936 KiB  
Article
Behavioural Characterisation of Macrod1 and Macrod2 Knockout Mice
by Kerryanne Crawford, Peter L. Oliver, Thomas Agnew, Benjamin H. M. Hunn and Ivan Ahel
Cells 2021, 10(2), 368; https://doi.org/10.3390/cells10020368 - 10 Feb 2021
Cited by 12 | Viewed by 4677
Abstract
Adenosine diphosphate ribosylation (ADP-ribosylation; ADPr), the addition of ADP-ribose moieties onto proteins and nucleic acids, is a highly conserved modification involved in a wide range of cellular functions, from viral defence, DNA damage response (DDR), metabolism, carcinogenesis and neurobiology. Here we study MACROD1 [...] Read more.
Adenosine diphosphate ribosylation (ADP-ribosylation; ADPr), the addition of ADP-ribose moieties onto proteins and nucleic acids, is a highly conserved modification involved in a wide range of cellular functions, from viral defence, DNA damage response (DDR), metabolism, carcinogenesis and neurobiology. Here we study MACROD1 and MACROD2 (mono-ADP-ribosylhydrolases 1 and 2), two of the least well-understood ADPr-mono-hydrolases. MACROD1 has been reported to be largely localized to the mitochondria, while the MACROD2 genomic locus has been associated with various neurological conditions such as autism, attention deficit hyperactivity disorder (ADHD) and schizophrenia; yet the potential significance of disrupting these proteins in the context of mammalian behaviour is unknown. Therefore, here we analysed both Macrod1 and Macrod2 gene knockout (KO) mouse models in a battery of well-defined, spontaneous behavioural testing paradigms. Loss of Macrod1 resulted in a female-specific motor-coordination defect, whereas Macrod2 disruption was associated with hyperactivity that became more pronounced with age, in combination with a bradykinesia-like gait. These data reveal new insights into the importance of ADPr-mono-hydrolases in aspects of behaviour associated with both mitochondrial and neuropsychiatric disorders. Full article
(This article belongs to the Special Issue Protein Mono-ADP-Ribosylation in the Control of Cell Functions)
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19 pages, 27049 KiB  
Article
Post-Transcriptional Regulation of PARP7 Protein Stability Is Controlled by Androgen Signaling
by Teddy Kamata, Chun-Song Yang, Tiffany A. Melhuish, Henry F. Frierson Jr., David Wotton and Bryce M. Paschal
Cells 2021, 10(2), 363; https://doi.org/10.3390/cells10020363 - 9 Feb 2021
Cited by 18 | Viewed by 5154
Abstract
Poly-ADP-ribose polymerases (PARPs) are enzymes that catalyze ADP-ribosylation and play critical roles in normal and disease settings. The PARP family member, PARP7, is a mono-ADP-ribosyltransferase that has been suggested to play a tumor suppressive role in breast, ovarian, and colorectal cancer. Here, we [...] Read more.
Poly-ADP-ribose polymerases (PARPs) are enzymes that catalyze ADP-ribosylation and play critical roles in normal and disease settings. The PARP family member, PARP7, is a mono-ADP-ribosyltransferase that has been suggested to play a tumor suppressive role in breast, ovarian, and colorectal cancer. Here, we have investigated how androgen signaling regulates PARP7 homeostasis in prostate cancer cells, where PARP7 is a direct target gene of AR. We found that the PARP7 protein is extremely short-lived, with a half-life of 4.5 min. We show that in addition to its transcriptional regulation by AR, PARP7 is subject to androgen-dependent post-transcriptional regulation that increases its half-life to 25.6 min. This contrasts with PARP1, PARP2, PARP9, and PARP14, which do not display rapid turnover and are not regulated by androgen signaling. Androgen- and AR-dependent stabilization of PARP7 leads to accumulation in the nucleus, which we suggest is a major site of action. Mutations in the catalytic domain, the Cys3His1 zinc finger, and WWE (tryptophan–tryptophan–glutamate) domains in PARP7 each reduce the degradation rate of PARP7, suggesting the overall structure of the protein is tuned for its rapid turnover. Our finding that PARP7 is regulated by AR signaling both transcriptionally and post-transcriptionally in prostate cancer cells suggests the dosage of PARP7 protein is subject to tight regulation. Full article
(This article belongs to the Special Issue Protein Mono-ADP-Ribosylation in the Control of Cell Functions)
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Review

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25 pages, 940 KiB  
Review
Uncovering the Invisible: Mono-ADP-ribosylation Moved into the Spotlight
by Ann-Katrin Hopp and Michael O. Hottiger
Cells 2021, 10(3), 680; https://doi.org/10.3390/cells10030680 - 19 Mar 2021
Cited by 25 | Viewed by 5815
Abstract
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 [...] Read more.
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. These tools have significantly enhanced our current understanding of how intracellular NAD dynamics contribute to the regulation of ADP-ribosylation as well as to how mono-ADP-ribosylation integrates into various cellular processes. Here, we discuss the recent technological advances, as well as associated new biological findings and concepts. Full article
(This article belongs to the Special Issue Protein Mono-ADP-Ribosylation in the Control of Cell Functions)
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21 pages, 2876 KiB  
Review
MARTs and MARylation in the Cytosol: Biological Functions, Mechanisms of Action, and Therapeutic Potential
by Sridevi Challa, MiKayla S. Stokes and W. Lee Kraus
Cells 2021, 10(2), 313; https://doi.org/10.3390/cells10020313 - 3 Feb 2021
Cited by 47 | Viewed by 6450
Abstract
Mono(ADP-ribosyl)ation (MARylation) is a regulatory post-translational modification of proteins that controls their functions through a variety of mechanisms. MARylation is catalyzed by mono(ADP-ribosyl) transferase (MART) enzymes, a subclass of the poly(ADP-ribosyl) polymerase (PARP) family of enzymes. Although the role of PARPs and poly(ADP-ribosyl)ation [...] Read more.
Mono(ADP-ribosyl)ation (MARylation) is a regulatory post-translational modification of proteins that controls their functions through a variety of mechanisms. MARylation is catalyzed by mono(ADP-ribosyl) transferase (MART) enzymes, a subclass of the poly(ADP-ribosyl) polymerase (PARP) family of enzymes. Although the role of PARPs and poly(ADP-ribosyl)ation (PARylation) in cellular pathways, such as DNA repair and transcription, is well studied, the role of MARylation and MARTs (i.e., the PARP ‘monoenzymes’) are not well understood. Moreover, compared to PARPs, the development of MART-targeted therapeutics is in its infancy. Recent studies are beginning to shed light on the structural features, catalytic targets, and biological functions of MARTs. The development of new technologies to study MARTs have uncovered essential roles for these enzymes in the regulation of cellular processes, such as RNA metabolism, cellular transport, focal adhesion, and stress responses. These insights have increased our understanding of the biological functions of MARTs in cancers, neuronal development, and immune responses. Furthermore, several novel inhibitors of MARTs have been developed and are nearing clinical utility. In this review, we summarize the biological functions and molecular mechanisms of MARTs and MARylation, as well as recent advances in technology that have enabled detection and inhibition of their activity. We emphasize PARP-7, which is at the forefront of the MART subfamily with respect to understanding its biological roles and the development of therapeutically useful inhibitors. Collectively, the available studies reveal a growing understanding of the biochemistry, chemical biology, physiology, and pathology of MARTs. Full article
(This article belongs to the Special Issue Protein Mono-ADP-Ribosylation in the Control of Cell Functions)
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25 pages, 1269 KiB  
Review
Mono(ADP-ribosyl)ation Enzymes and NAD+ Metabolism: A Focus on Diseases and Therapeutic Perspectives
by Palmiro Poltronieri, Angela Celetti and Luca Palazzo
Cells 2021, 10(1), 128; https://doi.org/10.3390/cells10010128 - 11 Jan 2021
Cited by 17 | Viewed by 6015
Abstract
Mono(ADP-ribose) transferases and mono(ADP-ribosyl)ating sirtuins use NAD+ to perform the mono(ADP-ribosyl)ation, a simple form of post-translational modification of proteins and, in some cases, of nucleic acids. The availability of NAD+ is a limiting step and an essential requisite for NAD+ [...] Read more.
Mono(ADP-ribose) transferases and mono(ADP-ribosyl)ating sirtuins use NAD+ to perform the mono(ADP-ribosyl)ation, a simple form of post-translational modification of proteins and, in some cases, of nucleic acids. The availability of NAD+ is a limiting step and an essential requisite for NAD+ consuming enzymes. The synthesis and degradation of NAD+, as well as the transport of its key intermediates among cell compartments, play a vital role in the maintenance of optimal NAD+ levels, which are essential for the regulation of NAD+-utilizing enzymes. In this review, we provide an overview of the current knowledge of NAD+ metabolism, highlighting the functional liaison with mono(ADP-ribosyl)ating enzymes, such as the well-known ARTD10 (also named PARP10), SIRT6, and SIRT7. To this aim, we discuss the link of these enzymes with NAD+ metabolism and chronic diseases, such as cancer, degenerative disorders and aging. Full article
(This article belongs to the Special Issue Protein Mono-ADP-Ribosylation in the Control of Cell Functions)
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