Suppression of ADP-ribosylation reversal triggers cell vulnerability to alkylating agents.

The ADP-ribosyl hydrolases PARG and ARH3 counteract PARP enzymatic activity by removing ADP-ribosylation. PARG and ARH3 activities have a synthetic lethal effect; however, the specific molecular mechanisms underlying this response remain unknown. Here, we show that the PARG and ARH3 synthetic lethality is enhanced further in the presence of DNA alkylating agents, suggesting that the inability to revert ADP-ribosylation primarily affects the repair of alkylated DNA bases.

Reversal of tyrosine-linked ADP-ribosylation by ARH3 and PARG.

ADP-ribosylation is an ancient posttranslational modification with exceptional versatility in terms of breadth of modification targets including at least seven different amino acid side chains, various moieties on nucleic acids, and a variety of small chemical compounds. The spatiotemporal signaling dynamic of the different modification variations is tightly regulated and depends on the writers, erases, and readers of each type. Among these, tyrosine ADP-ribosylation (Tyr-ADPr) has been consistently detected as a novel modification type, but systematic analysis of its potential physiological role, modification establishment, and reversal are still lacking.

Author Correction: PARP14 and PARP9/DTX3L regulate interferon-induced ADP-ribosylation.

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Histone ADP-ribosylation promotes resistance to PARP inhibitors by facilitating PARP1 release from DNA lesions.

Poly(ADP-ribose) polymerase 1 (PARP1) has emerged as a central target for cancer therapies due to the ability of PARP inhibitors to specifically kill tumors deficient for DNA repair by homologous recombination. Upon DNA damage, PARP1 quickly binds to DNA breaks and triggers ADP-ribosylation signaling. ADP-ribosylation is important for the recruitment of various factors to sites of damage, as well as for the timely dissociation of PARP1 from DNA breaks.

PARP14 and PARP9/DTX3L regulate interferon-induced ADP-ribosylation.

PARP-catalysed ADP-ribosylation (ADPr) is important in regulating various cellular pathways. Until recently, PARP-dependent mono-ADP-ribosylation has been poorly understood due to the lack of sensitive detection methods. Here, we utilised an improved antibody to detect mono-ADP-ribosylation.

Finding of an Unusually Colored Sporocyst of the Genus Leucochloridium in a Succinea putris Snail.

A Leucochloridium sp. Carus, 1835 sporocyst with a mature colored broodsac was found in a Succinea putris L., 1758 snail in the Boksitogorsk district of Leningrad Region (Russia).

ADP-ribosylation from molecular mechanisms to therapeutic implications.

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.

PARP14 is a PARP with both ADP-ribosyl transferase and hydrolase activities.

PARP14 is a mono-ADP-ribosyl transferase involved in the control of immunity, transcription, and DNA replication stress management. However, little is known about the ADP-ribosylation activity of PARP14, including its substrate specificity or how PARP14-dependent ADP-ribosylation is reversed. We show that PARP14 is a dual-function enzyme with both ADP-ribosyl transferase and hydrolase activity acting on both protein and nucleic acid substrates.

The interplay of TARG1 and PARG protects against genomic instability.

The timely removal of ADP-ribosylation is crucial for efficient DNA repair. However, much remains to be discovered about ADP-ribosylhydrolases. Here, we characterize the physiological role of TARG1, an ADP-ribosylhydrolase that removes aspartate/glutamate-linked ADP-ribosylation.

Genotypic and morphological diversity of trematodes Leucochloridium paradoxum.

The sporocysts of the trematode Leucochloridium paradoxum parasitise land snails Succinea putris. The sporocysts form broodsacs whose tegument contains green and brown pigments. The colouration changes during maturation.

The transcriptomic analysis of Planorbarius corneus hemocytes (Gastropoda) naturally infected with Bilharziella polonica (Schistosomatidae).

The study of molluscan innate immunity is essential for understanding the evolution of the immune system. An advance in the knowledge of their immune system can be achieved by increasing the number of model species. Our study focuses on the immunity of Planorbarius corneus, a pulmonate snail widely distributed in Eurasia.

The regulatory landscape of the human HPF1- and ARH3-dependent ADP-ribosylome.

Despite the involvement of Poly(ADP-ribose) polymerase-1 (PARP1) in many important biological pathways, the target residues of PARP1-mediated ADP-ribosylation remain ambiguous. To explicate the ADP-ribosylation regulome, we analyze human cells depleted for key regulators of PARP1 activity, histone PARylation factor 1 (HPF1) and ADP-ribosylhydrolase 3 (ARH3). Using quantitative proteomics, we characterize 1,596 ADP-ribosylation sites, displaying up to 1000-fold regulation across the investigated knockout cells.

Biallelic mutations in complex neuropathy affect ADP ribosylation and DNA damage response.

ADP ribosylation is a reversible posttranslational modification mediated by poly(ADP-ribose)transferases (e.g., PARP1) and (ADP-ribosyl)hydrolases (e.

Serine-linked PARP1 auto-modification controls PARP inhibitor response.

Poly(ADP-ribose) polymerase 1 (PARP1) and PARP2 are recruited and activated by DNA damage, resulting in ADP-ribosylation at numerous sites, both within PARP1 itself and in other proteins. Several PARP1 and PARP2 inhibitors are currently employed in the clinic or undergoing trials for treatment of various cancers. These drugs act primarily by trapping PARP1 on damaged chromatin, which can lead to cell death, especially in cells with DNA repair defects.

ADP-ribosylation of DNA and RNA.

ADP-ribosylation is a chemical modification of macromolecules found across all domains of life and known to regulate a variety of cellular processes. Notably, it has a well-established role in the DNA damage response. While it was historically known as a post-translational modification of proteins, recent studies have shown that nucleic acids can also serve as substrates of reversible ADP-ribosylation.

Simple and Efficient Protocol for Subcellular Fractionation of Normal and Apoptotic Cells.

Subcellular fractionation approaches remain an indispensable tool among a large number of biochemical methods to facilitate the study of specific intracellular events and characterization of protein functions. During apoptosis, the best-known form of programmed cell death, numerous proteins are translocated into and from the nucleus. Therefore, suitable biochemical techniques for the subcellular fractionation of apoptotic cells are required.

Pathogenic ARH3 mutations result in ADP-ribose chromatin scars during DNA strand break repair.

Neurodegeneration is a common hallmark of individuals with hereditary defects in DNA single-strand break repair; a process regulated by poly(ADP-ribose) metabolism. Recently, mutations in the ARH3 (ADPRHL2) hydrolase that removes ADP-ribose from proteins have been associated with neurodegenerative disease. Here, we show that ARH3-mutated patient cells accumulate mono(ADP-ribose) scars on core histones that are a molecular memory of recently repaired DNA single-strand breaks.

The DNA-damage response and nuclear events as regulators of nonapoptotic forms of cell death.

The maintenance of genome stability is essential for the cell as the integrity of genomic information guaranties reproduction of a whole organism. DNA damage occurring in response to different natural and nonnatural stimuli (errors in DNA replication, UV radiation, chemical agents, etc.) is normally detected by special cellular machinery that induces DNA repair.

Interplay of Histone Marks with Serine ADP-Ribosylation.

Serine ADP-ribosylation (Ser-ADPr) is a recently discovered protein modification that is catalyzed by PARP1 and PARP2 when in complex with the eponymous histone PARylation factor 1 (HPF1). In addition to numerous other targets, core histone tails are primary acceptors of Ser-ADPr in the DNA damage response. Here, we show that specific canonical histone marks interfere with Ser-ADPr of neighboring residues and vice versa.

Apoptosis regulation by subcellular relocation of caspases.

The cleavage of nuclear proteins by caspases promotes nuclear breakdown and, therefore, plays a key role in apoptosis execution. However, the detailed molecular mechanisms of these events remain unclear. To get more insights into the mechanisms of nuclear events during apoptosis we set up a rapid fractionation protocol for the separation of the cytoplasmic and nuclear fractions of cells undergoing cisplatin-induced apoptosis.

Alterations in the nucleocytoplasmic transport in apoptosis: Caspases lead the way.

Apoptosis is a mode of regulated cell death that is indispensable for the morphogenesis, development and homeostasis of multicellular organisms. Caspases are cysteine-dependent aspartate-specific proteases, which function as initiators and executors of apoptosis. Caspases are cytosolic proteins that can cleave substrates located in different intracellular compartments during apoptosis.

Serine is the major residue for ADP-ribosylation upon DNA damage.

Poly(ADP-ribose) polymerases (PARPs) are a family of enzymes that synthesise ADP-ribosylation (ADPr), a reversible modification of proteins that regulates many different cellular processes. Several mammalian PARPs are known to regulate the DNA damage response, but it is not clear which amino acids in proteins are the primary ADPr targets. Previously, we reported that ARH3 reverses the newly discovered type of ADPr (ADPr on serine residues; Ser-ADPr) and developed tools to analyse this modification (Fontana et al.