scholarly journals Uncovering the Invisible: Mono-ADP-ribosylation Moved into the Spotlight

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 680
Author(s):  
Ann-Katrin Hopp ◽  
Michael O. Hottiger
Keyword(s):  
Nucleic Acids ◽  
Nicotinamide Adenine Dinucleotide ◽  
Physiological Function ◽  
Adenosine Diphosphate ◽  
Current Understanding ◽  
Post Translational Modification ◽  
Adp Ribosylation ◽  
Cellular Processes ◽  
The Past ◽  
Technological Advances

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.

scholarly journals DEPTOR in Skeletal Development and Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Jose Miguel Perez-Tejeiro ◽  
Fabiana Csukasi
Keyword(s):  
Skeletal Development ◽  
Negative Regulator ◽  
Current Understanding ◽  
Skeletal Biology ◽  
Interacting Protein ◽  
Cellular Processes ◽  
The Past ◽  
Mechanistic Target Of Rapamycin ◽  
Evolutionarily Conserved ◽  
Important Regulator

Discovered in 2009, the DEP-domain containing mTOR-interacting protein, DEPTOR, is a known regulator of the mechanistic target of rapamycin (mTOR), an evolutionarily conserved kinase that regulates diverse cellular processes in response to environmental stimuli. DEPTOR was originally identified as a negative regulator of mTOR complexes 1 (mTORC1) and 2 (mTORC2). However, recent discoveries have started to unravel the roles of DEPTOR in mTOR-independent responses. In the past few years, mTOR emerged as an important regulator of skeletal development, growth, and homeostasis; the dysregulation of its activity contributes to the development of several skeletal diseases, both chronic and genetic. Even more recently, several groups have reported on the relevance of DEPTOR in skeletal biology through its action on mTOR-dependent and mTOR-independent pathways. In this review, we summarize the current understanding of DEPTOR in skeletal development and disease.

Molecular context of ADP-ribosylation in schistosomes for drug discovery and vaccine development

2020 ◽  
Vol 17 ◽  
Author(s):  
Amandla Chutshela ◽  
Priscilla Masamba ◽  
Babatunji Emmanuel Oyinloye ◽  
Abidemi Paul Kappo
Keyword(s):  
Drug Discovery ◽  
Drug Targets ◽  
Vaccine Development ◽  
Neglected Tropical Diseases ◽  
Adenosine Diphosphate ◽  
Biological Processes ◽  
Post Translational Modification ◽  
Adp Ribosylation ◽  
Molecular Context ◽  
Living Organisms

: Schistosome infection is regarded as one of the most important and neglected tropical diseases associated with poor sanitation. Like other living organisms, schistosomes employ multiple biological processes, of which some are regulated by a post-translational modification called Adenosine diphosphate-ribosylation (ADP-ribosylation), catalyzed by ADPribosyltransferases. ADP-ribosylation is the addition of ADP-ribose moieties from nicotinamide adenine dinucleotide (NAD+) to various targets, which include proteins and nucleotides. It is crucial in biological processes such as DNA repair, apoptosis, carbohydrate metabolism and catabolism. In the absence of a vaccine against schistosomiasis, this becomes a promising pathway in the identification of drug targets against various forms of this infection. The tegument of the worm is an encouraging immunogenic target for anti-schistosomal vaccine development. Vaccinology, molecular modeling and target-based drug discovery strategies have been used for years in drug discovery and for vaccine development. In this paper, we outline ADP-ribosylation and other different approaches to drug discovery and vaccine development against schistosomiasis.

scholarly journals Role of APD-Ribosylation in Bone Health and Disease

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1201 ◽  
Author(s):  
Wang ◽  
Mbalaviele
Keyword(s):  
Bone Development ◽  
Adenosine Diphosphate ◽  
Signaling Networks ◽  
Post Translational Modification ◽  
Cell Behaviors ◽  
Adp Ribosylation ◽  
Protein Functions ◽  
Health And Disease ◽  
Underlying Mechanisms

The transfer of adenosine diphosphate (ADP)-ribose unit(s) from nicotinamide adenine dinucleotide (NAD+) to acceptor proteins is known as ADP-ribosylation. This post-translational modification (PTM) unavoidably alters protein functions and signaling networks, thereby impacting cell behaviors and tissue outcomes. As a ubiquitous mechanism, ADP-ribosylation affects multiple tissues, including bones, as abnormal ADP-ribosylation compromises bone development and remodeling. In this review, we describe the effects of ADP-ribosylation in bone development and maintenance, and highlight the underlying mechanisms.

scholarly journals A ribose-functionalized NAD+ with unexpected high activity and selectivity for protein poly-ADP-ribosylation

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Xiao-Nan Zhang ◽  
Qinqin Cheng ◽  
Jingwen Chen ◽  
Albert T. Lam ◽  
Yanran Lu ◽  
...  
Keyword(s):  
High Activity ◽  
Nicotinamide Adenine Dinucleotide ◽  
High Efficiency ◽  
Mitochondrial Protein ◽  
Chemoenzymatic Synthesis ◽  
Direct Visualization ◽  
Terminal Alkyne ◽  
Post Translational Modification ◽  
Nicotinamide Riboside ◽  
Adp Ribosylation

Abstract Nicotinamide adenine dinucleotide (NAD+)-dependent ADP-ribosylation plays important roles in physiology and pathophysiology. It has been challenging to study this key type of enzymatic post-translational modification in particular for protein poly-ADP-ribosylation (PARylation). Here we explore chemical and chemoenzymatic synthesis of NAD+ analogues with ribose functionalized by terminal alkyne and azido groups. Our results demonstrate that azido substitution at 3′-OH of nicotinamide riboside enables enzymatic synthesis of an NAD+ analogue with high efficiency and yields. Notably, the generated 3′-azido NAD+ exhibits unexpected high activity and specificity for protein PARylation catalyzed by human poly-ADP-ribose polymerase 1 (PARP1) and PARP2. And its derived poly-ADP-ribose polymers show increased resistance to human poly(ADP-ribose) glycohydrolase-mediated degradation. These unique properties lead to enhanced labeling of protein PARylation by 3′-azido NAD+ in the cellular contexts and facilitate direct visualization and labeling of mitochondrial protein PARylation. The 3′-azido NAD+ provides an important tool for studying cellular PARylation.

scholarly journals Epigenetics of Aging and Aging-Associated Diseases

2021 ◽  
Vol 22 (1) ◽  
pp. 401
Author(s):  
Dominik Saul ◽  
Robyn Laura Kosinsky
Keyword(s):  
Neurodegenerative Disorders ◽  
Physiological Function ◽  
Living Organism ◽  
Histone Variants ◽  
Chromatin Accessibility ◽  
Epigenetic Changes ◽  
Cellular Processes ◽  
The Past ◽  
Epigenetic Events ◽  
Expression Activity

Aging represents the multifactorial decline in physiological function of every living organism. Over the past decades, several hallmarks of aging have been defined, including epigenetic deregulation. Indeed, multiple epigenetic events were found altered across different species during aging. Epigenetic changes directly contributing to aging and aging-related diseases include the accumulation of histone variants, changes in chromatin accessibility, loss of histones and heterochromatin, aberrant histone modifications, and deregulated expression/activity of miRNAs. As a consequence, cellular processes are affected, which results in the development or progression of several human pathologies, including cancer, diabetes, osteoporosis, and neurodegenerative disorders. In this review, we focus on epigenetic mechanisms underlying aging-related processes in various species and describe how these deregulations contribute to human diseases.

scholarly journals The Critical Role of PARPs in Regulating Innate Immune Responses

2021 ◽  
Vol 12 ◽  
Author(s):  
Huifang Zhu ◽  
Yan-Dong Tang ◽  
Guoqing Zhan ◽  
Chenhe Su ◽  
Chunfu Zheng
Keyword(s):  
Immune Responses ◽  
Critical Role ◽  
Molecular Targets ◽  
Adenosine Diphosphate ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Adp Ribosylation

Poly (adenosine diphosphate-ribose) polymerases (PARPs) are a family of proteins responsible for transferring ADP-ribose groups to target proteins to initiate the ADP-ribosylation, a highly conserved and fundamental post-translational modification in all organisms. PARPs play important roles in various cellular functions, including regulating chromatin structure, transcription, replication, recombination, and DNA repair. Several studies have recently converged on the widespread involvement of PARPs and ADP-Ribosylation reaction in mammalian innate immunity. Here, we provide an overview of the emerging roles of PARPs family and ADP-ribosylation in regulating the host’s innate immune responses involved in cancers, pathogenic infections, and inflammations, which will help discover and design new molecular targets for cancers, pathogenic infections, and inflammations.

scholarly journals An advanced strategy for comprehensive profiling of ADP-ribosylation sites using mass spectrometry-based proteomics

2018 ◽  
Author(s):  
Ivo A. Hendriks ◽  
Sara C. Larsen ◽  
Michael L. Nielsen
Keyword(s):  
Electron Transfer ◽  
Electron Transfer Dissociation ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Functional Enrichment ◽  
Post Translational Modification ◽  
Tyrosine Residues ◽  
Adp Ribosylation ◽  
Cellular Processes ◽  
Nuclear Proteome

ABSTRACTADP-ribosylation is a widespread post-translational modification (PTM) with crucial functions in many cellular processes. Here, we describe an in-depth ADP-ribosylome using our Af1521-based proteomics methodology for comprehensive profiling of ADP-ribosylation sites, by systematically assessing complementary proteolytic digestions and precursor fragmentation through application of electron-transfer higher-energy collisional dissociation (EThcD) and electron transfer dissociation (ETD), respectively. While ETD spectra yielded higher identification scores, EThcD generally proved superior to ETD in identification and localization of ADP-ribosylation sites regardless of protease employed. Notwithstanding, the propensities of complementary proteases and fragmentation methods expanded the detectable repertoire of ADP-ribosylation to an unprecedented depth. This system-wide profiling of the ADP-ribosylome in HeLa cells subjected to DNA damage uncovered >11,000 unique ADP-ribosylated peptides mapping to >7,000 ADP-ribosylation sites, in total modifying over one-third of the human nuclear proteome and highlighting the vast scope of this PTM. High-resolution MS/MS spectra enabled identification of dozens of proteins concomitantly modified by ADP-ribosylation and phosphorylation, revealing a considerable degree of crosstalk on histones. ADP-ribosylation was confidently localized to various amino acid residue types, including less abundantly modified residues, with hundreds of ADP-ribosylation sites pinpointed on histidine, arginine, and tyrosine residues. Functional enrichment analysis suggested modification of these specific residue types is directed in a spatial manner, with tyrosine ADP-ribosylation linked to the ribosome, arginine ADP-ribosylation linked to the endoplasmic reticulum, and histidine ADP-ribosylation linked to the mitochondrion.

scholarly journals Post-translational lysine ac(et)ylation in health, ageing and disease

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Anna-Theresa Blasl ◽  
Sabrina Schulze ◽  
Chuan Qin ◽  
Leonie G. Graf ◽  
Robert Vogt ◽  
...  
Keyword(s):  
Protein Function ◽  
Molecular Mechanisms ◽  
Research Field ◽  
Ageing Process ◽  
Post Translational Modification ◽  
Direct Role ◽  
Translational Machinery ◽  
Beneficial Effects ◽  
Cellular Processes ◽  
Technological Advances

Abstract The acetylation/acylation (ac(et)ylation) of lysine side chains is a dynamic post-translational modification (PTM) regulating fundamental cellular processes with implications on the organisms’ ageing process: metabolism, transcription, translation, cell proliferation, regulation of the cytoskeleton and DNA damage repair. First identified to occur on histones, later studies revealed the presence of lysine ac(et)ylation in organisms of all kingdoms of life, in proteins covering all essential cellular processes. A remarkable finding showed that the NAD+-dependent sirtuin deacetylase Sir2 has an impact on replicative lifespan in Saccharomyces cerevisiae suggesting that lysine acetylation has a direct role in the ageing process. Later studies identified sirtuins as mediators for beneficial effects of caloric/dietary restriction on the organisms’ health- or lifespan. However, the molecular mechanisms underlying these effects are only incompletely understood. Progress in mass-spectrometry, structural biology, synthetic and semi-synthetic biology deepened our understanding of this PTM. This review summarizes recent developments in the research field. It shows how lysine ac(et)ylation regulates protein function, how it is regulated enzymatically and non-enzymatically, how a dysfunction in this post-translational machinery contributes to disease development. A focus is set on sirtuins and lysine acyltransferases as these are direct sensors and mediators of the cellular metabolic state. Finally, this review highlights technological advances to study lysine ac(et)ylation.

scholarly journals Chemical Synthesis of Linear ADP-ribose Oligomers up to Pentamer and their Binding to the Oncogenic Helicase ALC1

2021 ◽  
Author(s):  
Qiang Liu ◽  
Gunnar Knobloch ◽  
Jim Voorneveld ◽  
Nico Meeuwenoord ◽  
Herman S. Overkleeft ◽  
...  
Keyword(s):  
Chemical Synthesis ◽  
Post Translational Modification ◽  
Adp Ribosylation ◽  
Cellular Processes

ADP-ribosylation is a pivotal post-translational modification that mediates various important cellular processes producing negatively charged biopolymer, poly (ADP-ribose), the functions of which need further elucidation. Toward this end, the availability...

scholarly journals Mapping physiological ADP-ribosylation using Activated Ion Electron Transfer Dissociation (AI-ETD)

2020 ◽  
Author(s):  
Sara C. Buch-Larsen ◽  
Ivo A. Hendriks ◽  
Jean M. Lodge ◽  
Martin Rykær ◽  
Benjamin Furtwängler ◽  
...  
Keyword(s):  
Electron Transfer ◽  
Electron Transfer Dissociation ◽  
Post Translational Modification ◽  
Physiological Regulation ◽  
Physiological Conditions ◽  
Adp Ribosylation ◽  
Cellular Processes ◽  
Wide Range ◽  
Enrichment Strategy

SUMMARYADP-ribosylation (ADPr) is a post-translational modification that plays pivotal roles in a wide range of cellular processes. Mass spectrometry (MS)-based analysis of ADPr under physiological conditions, without relying on genetic or chemical perturbation, has been hindered by technical limitations. Here, we describe the applicability of Activated Ion Electron Transfer Dissociation (AI-ETD) for MS-based proteomics analysis of physiological ADPr using our unbiased Af1521 enrichment strategy. To benchmark AI-ETD, we profiled 9,000 ADPr peptides mapping to >5,000 unique ADPr sites from a limited number of cells exposed to oxidative stress, corresponding to 120% and 28% more ADPr peptides compared to contemporary strategies using ETD and EThcD, respectively. Under physiological conditions AI-ETD identified 450 ADPr sites on low-abundant proteins, including in vivo cysteine auto-modifications on PARP8 and tyrosine auto-modifications on PARP14, hinting at specialist enzymatic functions for these enzymes. Collectively, our data provides new insights into the physiological regulation of ADP-ribosylation.

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