Novel drug targets for personalized precision medicine in relapsed/refractory diffuse large B-cell lymphoma: a comprehensive review.

Diffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous lymphoid malignancy and the most common subtype of non-Hodgkin's lymphoma in adults, with one of the highest mortality rates in most developed areas of the world. More than half of DLBLC patients can be cured with standard R-CHOP regimens, however approximately 30 to 40 % of patients will develop relapsed/refractory disease that remains a major cause of morbidity and mortality due to the limited therapeutic options.Recent advances in gene expression profiling have led to the identification of at least three distinct molecular subtypes of DLBCL: a germinal center B cell-like subtype, an activated B cell-like subtype, and a primary mediastinal B-cell lymphoma subtype.

DTX3L and ARTD9 inhibit IRF1 expression and mediate in cooperation with ARTD8 survival and proliferation of metastatic prostate cancer cells.

Background: Prostate cancer (PCa) is one of the leading causes of cancer-related mortality and morbidity in the aging male population and represents the most frequently diagnosed malignancy in men around the world. The Deltex (DTX)-3-like E3 ubiquitin ligase (DTX3L), also known as B-lymphoma and BAL-associated protein (BBAP), was originally identified as a binding partner of the diphtheria-toxin-like macrodomain containing ADP-ribosyltransferase-9 (ARTD9), also known as BAL1 and PARP9. We have previously demonstrated that ARTD9 acts as a novel oncogenic survival factor in high-risk, chemo-resistant, diffuse large B cell lymphoma (DLBCL).

Characterization of recombinant human and bovine thyroid-stimulating hormone preparations by mass spectrometry and determination of their endotoxin content.

Background: The TSH stimulation test to confirm canine hypothyroidism is commonly performed using a recombinant human TSH (rhTSH), as up to date, canine TSH is not yet commercially available. Limiting factors for the use of rhTSH are its high costs and occasional difficulties in product availability. Less expensive bovine TSH preparations (bTSH) purified from bovine pituitary glands are readily commercially available.

BAL1/ARTD9 represses the anti-proliferative and pro-apoptotic IFNγ-STAT1-IRF1-p53 axis in diffuse large B-cell lymphoma.

The B-aggressive lymphoma-1 protein and ADP-ribosyltransferase BAL1/ARTD9 has been recently identified as a risk-related gene product in aggressive diffuse large B-cell lymphoma (DLBCL). BAL1 is constitutively expressed in a subset of high-risk DLBCLs with an active host inflammatory response and has been suggested to be associated with interferon-related gene expression. Here we identify BAL1 as a novel oncogenic survival factor in DLBCL and show that constitutive overexpression of BAL1 in DLBCL tightly associates with intrinsic interferon-gamma (IFNγ) signaling and constitutive activity of signal transducer and activator of transcription (STAT)-1.

Macrodomain-containing proteins are new mono-ADP-ribosylhydrolases.

ADP-ribosylation is an important post-translational protein modification (PTM) that regulates diverse biological processes. ADP-ribosyltransferase diphtheria toxin-like 10 (ARTD10, also known as PARP10) mono-ADP-ribosylates acidic side chains and is one of eighteen ADP-ribosyltransferases that catalyze mono- or poly-ADP-ribosylation of target proteins. Currently, no enzyme is known that reverses ARTD10-catalyzed mono-ADP-ribosylation.

The zinc-finger domains of PARP1 cooperate to recognize DNA strand breaks.

Poly(ADP-ribose) polymerase 1 (PARP1) is a primary DNA damage sensor whose (ADP-ribose) polymerase activity is acutely regulated by interaction with DNA breaks. Upon activation at sites of DNA damage, PARP1 modifies itself and other proteins by covalent addition of long, branched polymers of ADP-ribose, which in turn recruit downstream DNA repair and chromatin remodeling factors. PARP1 recognizes DNA damage through its N-terminal DNA-binding domain (DBD), which consists of a tandem repeat of an unusual zinc-finger (ZnF) domain.

Inflammasome-activated caspase 7 cleaves PARP1 to enhance the expression of a subset of NF-κB target genes.

Caspase 1 is part of the inflammasome, which is assembled upon pathogen recognition, while caspases 3 and/or 7 are mediators of apoptotic and nonapoptotic functions. PARP1 cleavage is a hallmark of apoptosis yet not essential, suggesting it has another physiological role. Here we show that after LPS stimulation, caspase 7 is activated by caspase 1, translocates to the nucleus, and cleaves PARP1 at the promoters of a subset of NF-κB target genes negatively regulated by PARP1.

Poly(ADP-ribose) polymerase-1 protects from oxidative stress induced endothelial dysfunction.

Background: Generation of reactive oxygen species (ROS) is a key feature of vascular disease. Activation of the nuclear enzyme poly (adenosine diphosphate [ADP]-ribose) polymerase-1 (PARP-1) is a downstream effector of oxidative stress.

Methods: PARP-1(-/-) and PARP-1(+/+) mice were injected with paraquat (PQ; 10 mg/kg i.

Toward a unified nomenclature for mammalian ADP-ribosyltransferases.

ADP-ribosylation is a post-translational modification of proteins catalyzed by ADP-ribosyltransferases. It comprises the transfer of the ADP-ribose moiety from NAD+ to specific amino acid residues on substrate proteins or to ADP-ribose itself. Currently, 22 human genes encoding proteins that possess an ADP-ribosyltransferase catalytic domain are known.

A macrodomain-containing histone rearranges chromatin upon sensing PARP1 activation.

Poly-ADP-ribosylation is a post-translational modification catalyzed by PARP enzymes with roles in transcription and chromatin biology. Here we show that distinct macrodomains, including those of histone macroH2A1.1, are recruited to sites of PARP1 activation induced by laser-generated DNA damage.

Catalytic core of a membrane-associated eukaryotic polyphosphate polymerase.

Polyphosphate (polyP) occurs ubiquitously in cells, but its functions are poorly understood and its synthesis has only been characterized in bacteria. Using x-ray crystallography, we identified a eukaryotic polyphosphate polymerase within the membrane-integral vacuolar transporter chaperone (VTC) complex. A 2.

Molecular mechanism of poly(ADP-ribosyl)ation by PARP1 and identification of lysine residues as ADP-ribose acceptor sites.

Poly(ADP-ribose) polymerase 1 (PARP1) synthesizes poly(ADP-ribose) (PAR) using nicotinamide adenine dinucleotide (NAD) as a substrate. Despite intensive research on the cellular functions of PARP1, the molecular mechanism of PAR formation has not been comprehensively understood. In this study, we elucidate the molecular mechanisms of poly(ADP-ribosyl)ation and identify PAR acceptor sites.

The molecular "Jekyll and Hyde" duality of PARP1 in cell death and cell survival.

The current literature clearly indicates that PARP1 but also PARP2 play a pivotal role in modulating the cellular responses to stress. Genetic and pharmacological studies demonstrated that overactivation of PARP1 is a key mediator of programmed-necrotic cell death in vivo. PARP1 appears to be also involved in programmed cell death processes others than necrosis, such as apoptosis or macroautophagocytotic cell death.

Substrate-assisted catalysis by PARP10 limits its activity to mono-ADP-ribosylation.

ADP-ribosylation controls many processes, including transcription, DNA repair, and bacterial toxicity. ADP-ribosyltransferases and poly-ADP-ribose polymerases (PARPs) catalyze mono- and poly-ADP-ribosylation, respectively, and depend on a highly conserved glutamate residue in the active center for catalysis. However, there is an apparent absence of this glutamate for the recently described PARP6-PARP16, raising questions about how these enzymes function.

Importin alpha binding and nuclear localization of PARP-2 is dependent on lysine 36, which is located within a predicted classical NLS.

Background: The enzymes responsible for the synthesis of poly-ADP-ribose are named poly-ADP-ribose polymerases (PARP). PARP-2 is a nuclear protein, which regulates a variety of cellular functions that are mainly controlled by protein-protein interactions. A previously described non-conventional bipartite nuclear localization sequence (NLS) lies in the amino-terminal DNA binding domain of PARP-2 between amino acids 1-69; however, this targeting sequence has not been experimentally examined or validated.

Identification of lysines 36 and 37 of PARP-2 as targets for acetylation and auto-ADP-ribosylation.

Poly-ADP-ribose polymerase-2 (PARP-2) was described to regulate cellular functions comprising DNA surveillance, inflammation and cell differentiation by co-regulating different transcription factors. Using an in vitro and in vivo approach, we identified PARP-2 as a new substrate for the histone acetyltransferases PCAF and GCN5L. Site directed mutagenesis indicated that lysines 36 and 37, located in the nuclear localization signal of PARP-2, are the main targets for PCAF and GCN5L activity in vitro.

Poly(ADP-ribose) polymerase 1 promotes tumor cell survival by coactivating hypoxia-inducible factor-1-dependent gene expression.

Hypoxia-inducible factor 1 (HIF-1) is the key transcription factor regulating hypoxia-dependent gene expression. Lack of oxygen stabilizes HIF-1, which in turn modulates the gene expression pattern to adapt cells to the hypoxic environment. Activation of HIF-1 is also detected in most solid tumors and supports tumor growth through the expression of target genes that are involved in processes like cell proliferation, energy metabolism, and oxygen delivery.

Protein arginine methyltransferase 1 coactivates NF-kappaB-dependent gene expression synergistically with CARM1 and PARP1.

Nuclear factor kappa B (NF-kappaB) plays an important role in the transcriptional regulation of genes involved in inflammation and cell survival. Transcriptional coactivators that methylate histones become increasingly important. Recently, we provided evidence that coactivator-associated arginine methyltransferase 1 (CARM1) is a transcriptional coactivator of NF-kappaB and functions as a promoter-specific regulator of NF-kappaB recruitment to chromatin.

PARP1 is required for adhesion molecule expression in atherogenesis.

Aims: Atherosclerosis is the leading cause of death in Western societies and a chronic inflammatory disease. However, the key mediators linking recruitment of inflammatory cells to atherogenesis remain poorly defined. Poly(ADP-ribose) polymerase 1 (PARP1) is a nuclear enzyme, which plays a role in acute inflammatory diseases.

The diverse biological roles of mammalian PARPS, a small but powerful family of poly-ADP-ribose polymerases.

Poly-ADP-ribose metabolism plays a mayor role in a wide range of biological processes, such as maintenance of genomic stability, transcriptional regulation, energy metabolism and cell death. Poly-ADP-ribose polymerases (PARPs) are an ancient family of enzymes, as evidenced by the poly-ADP-ribosylating activities reported in dinoflagellates and archaebacteria and by the identification of Parp-like genes in eubacterial and archaeabacterial genomes. Six genes encoding "bona fide" PARP enzymes have been identified in mammalians: PARP1, PARP2, PARP3, PARP4/vPARP, PARP5/Tankyrases-1 and PARP6/Tankyrases-2.

Yeast split-ubiquitin-based cytosolic screening system to detect interactions between transcriptionally active proteins.

Interactions between proteins are central to most biological processes; consequently, understanding the latter requires identification of all possible protein interactions within a cell. To extend the range of existing assays for the detection of protein interactions, we present a novel genetic screening assay, the cytosolic yeast two-hybrid system (cytoY2H), which is based on the split-ubiquitin technique and detects protein-protein interactions in the cytoplasm. We show that the assay can be applied to a wide range of proteins that are difficult to study in the classical yeast two-hybrid (Y2H) system, including transcription factors such as p53 and members of the NF-kappaB complex.

Methylation of DNA polymerase beta by protein arginine methyltransferase 1 regulates its binding to proliferating cell nuclear antigen.

DNA polymerase beta (pol beta) is a key player in DNA base excision repair (BER). Here, we describe the complex formation of pol beta with the protein arginine methyltransferase 1 (PRMT1). PRMT1 specifically methylated pol beta in vitro and in vivo.

Gene expression in synovial membrane cells after intraarticular delivery of plasmid-linked superparamagnetic iron oxide particles--a preliminary study in sheep.

This study evaluated in vivo gene delivery and subsequent gene expression within cells of the synovium in the presence of static and pulsating magnetic field application following intraarticular injection of superparamagnetic iron oxide nanoparticles linked to plasmids containing reporter genes encoding for fluorescent proteins. Plasmids encoding genes for either green fluorescent protein or red fluorescent protein were bound to superparamagnetic nanoparticles coated with polyethyleneimine. Larger (200-250 nm) and smaller (50 nm) nanoparticles were compared to evaluate the effects of size on transfection efficiency as well as any associated intraarticular reaction.

Nuclear ADP-ribosylation reactions in mammalian cells: where are we today and where are we going?

Since poly-ADP ribose was discovered over 40 years ago, there has been significant progress in research into the biology of mono- and poly-ADP-ribosylation reactions. During the last decade, it became clear that ADP-ribosylation reactions play important roles in a wide range of physiological and pathophysiological processes, including inter- and intracellular signaling, transcriptional regulation, DNA repair pathways and maintenance of genomic stability, telomere dynamics, cell differentiation and proliferation, and necrosis and apoptosis. ADP-ribosylation reactions are phylogenetically ancient and can be classified into four major groups: mono-ADP-ribosylation, poly-ADP-ribosylation, ADP-ribose cyclization, and formation of O-acetyl-ADP-ribose.