The Impact of Parps and ADP-Ribosylation on Inflammation and Host–Pathogen Interactions
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The Role of PARP1 in Monocyte and Macrophage
cells Review The Role of PARP1 in Monocyte and Macrophage Commitment and Specification: Future Perspectives and Limitations for the Treatment of Monocyte and Macrophage Relevant Diseases with PARP Inhibitors Maciej Sobczak 1, Marharyta Zyma 2 and Agnieszka Robaszkiewicz 1,* 1 Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland; [email protected] 2 Department of Immunopathology, Medical University of Lodz, 7/9 Zeligowskiego, Bldg 2, Rm177, 90-752 Lodz, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-42-6354449; Fax: +48-42-6354449 or +48-42-635-4473 Received: 4 August 2020; Accepted: 4 September 2020; Published: 6 September 2020 Abstract: Modulation of PARP1 expression, changes in its enzymatic activity, post-translational modifications, and inflammasome-dependent cleavage play an important role in the development of monocytes and numerous subtypes of highly specialized macrophages. Transcription of PARP1 is governed by the proliferation status of cells at each step of their development. Higher abundance of PARP1 in embryonic stem cells and in hematopoietic precursors supports their self-renewal and pluri-/multipotency, whereas a low level of the enzyme in monocytes determines the pattern of surface receptors and signal transducers that are functionally linked to the NFκB pathway. In macrophages, the involvement of PARP1 in regulation of transcription, signaling, inflammasome activity, metabolism, and redox balance supports macrophage polarization towards the pro-inflammatory phenotype (M1), which drives host defense against pathogens. On the other hand, it seems to limit the development of a variety of subsets of anti-inflammatory myeloid effectors (M2), which help to remove tissue debris and achieve healing. -
CD56+ T-Cells in Relation to Cytomegalovirus in Healthy Subjects and Kidney Transplant Patients
CD56+ T-cells in Relation to Cytomegalovirus in Healthy Subjects and Kidney Transplant Patients Institute of Infection and Global Health Department of Clinical Infection, Microbiology and Immunology Thesis submitted in accordance with the requirements of the University of Liverpool for the degree of Doctor in Philosophy by Mazen Mohammed Almehmadi December 2014 - 1 - Abstract Human T cells expressing CD56 are capable of tumour cell lysis following activation with interleukin-2 but their role in viral immunity has been less well studied. The work described in this thesis aimed to investigate CD56+ T-cells in relation to cytomegalovirus infection in healthy subjects and kidney transplant patients (KTPs). Proportions of CD56+ T cells were found to be highly significantly increased in healthy cytomegalovirus-seropositive (CMV+) compared to cytomegalovirus-seronegative (CMV-) subjects (8.38% ± 0.33 versus 3.29%± 0.33; P < 0.0001). In donor CMV-/recipient CMV- (D-/R-)- KTPs levels of CD56+ T cells were 1.9% ±0.35 versus 5.42% ±1.01 in D+/R- patients and 5.11% ±0.69 in R+ patients (P 0.0247 and < 0.0001 respectively). CD56+ T cells in both healthy CMV+ subjects and KTPs expressed markers of effector memory- RA T-cells (TEMRA) while in healthy CMV- subjects and D-/R- KTPs the phenotype was predominantly that of naïve T-cells. Other surface markers, CD8, CD4, CD58, CD57, CD94 and NKG2C were expressed by a significantly higher proportion of CD56+ T-cells in healthy CMV+ than CMV- subjects. Functional studies showed levels of pro-inflammatory cytokines IFN-γ and TNF-α, as well as granzyme B and CD107a were significantly higher in CD56+ T-cells from CMV+ than CMV- subjects following stimulation with CMV antigens. -
Poly(ADP-Ribose) Polymerase-1 (PARP1) and P53 Labelling Index Correlates with Tumour Grade in Meningiomas
Original article Poly(ADP-ribose) polymerase-1 (PARP1) and p53 labelling index correlates with tumour grade in meningiomas Tamás Csonka1, Balázs Murnyák1, Rita Szepesi2, Andrea Kurucz1, Álmos Klekner3, Tibor Hortobágyi1 1Division of Neuropathology, Institute of Pathology, 2Department of Neurology, 3Department of Neurosurgery, Faculty of Medicine, University of Debrecen, Debrecen, Hungary Folia Neuropathol 2014; 52 (2): 111-120 DOI: 10.5114/fn.2014.43782 Abstract Meningiomas are one of the most frequent intracranial tumours, with 13 histological types and three grades accord- ing to the 2007 WHO Classification of Tumours of the Central Nervous System. p53, as one of the most potent tumour suppressor proteins, plays a role in nearly 50% of human tumours. Poly(ADP-ribose) polymerase (PARP) is a DNA repair enzyme with high ATP demand. It plays a role in apoptosis by activating an apoptosis inducing factor, and in necrosis by consuming NAD+ and ATP. Only PARP1 has been investigated in detail in tumours out of the 17 members of the PARP superfamily; however, its role has not been studied in meningiomas yet. The aim of this study was to determine the role of p53 and PARP1 in meningiomas of different grade and to establish whether there is any correlation between the p53 and PARP1 expression. Both PARP1 and p53 have been expressed in all examined meningiomas. PARP1 labelled grade II tumours with a higher intensity as compared to grade I and III neoplasms, respectively. An increased p53 expression was noted in grade III meningiomas. There was no statistical correlation between p53 and PARP1 expression. Our data indicate that both PARP1 and p53 activation is a feature in menin- giomas of higher grade, PARP1 overexpression being an early, whereas p53 overexpression, a late event in tumour progression. -
PARP Inhibitors in Prostate Cancer–The Preclinical Rationale and Current Clinical Development
G C A T T A C G G C A T genes Review PARP Inhibitors in Prostate Cancer–the Preclinical Rationale and Current Clinical Development Verneri Virtanen 1, Kreetta Paunu 1, Johanna K. Ahlskog 2, Reka Varnai 3,4 , Csilla Sipeky 5 and Maria Sundvall 1,6,* 1 Institute of Biomedicine, and Cancer Research Laboratories, Western Cancer Centre FICAN West, University of Turku, FI-20520 Turku, Finland 2 Faculty of Science and Engineering, Åbo Akademi University, and Turku Bioscience, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland 3 Department of Primary Health Care, University of Pécs, H-7623 Pécs, Hungary 4 Faculty of Health Sciences, Doctoral School of Health Sciences, University of Pécs, H-7621 Pécs, Hungary 5 Institute of Biomedicine, University of Turku, FI-20520 Turku, Finland 6 Department of Oncology and Radiotherapy, Turku University Hospital, FI-20521 Turku, Finland * Correspondence: maria.sundvall@utu.fi; Tel.: +358-2-313-0000 Received: 3 June 2019; Accepted: 22 July 2019; Published: 26 July 2019 Abstract: Prostate cancer is globally the second most commonly diagnosed cancer type in men. Recent studies suggest that mutations in DNA repair genes are associated with aggressive forms of prostate cancer and castration resistance. Prostate cancer with DNA repair defects may be vulnerable to therapeutic targeting by Poly(ADP-ribose) polymerase (PARP) inhibitors. PARP enzymes modify target proteins with ADP-ribose in a process called PARylation and are in particular involved in single strand break repair. The rationale behind the clinical trials that led to the current use of PARP inhibitors to treat cancer was to target the dependence of BRCA-mutant cancer cells on the PARP-associated repair pathway due to deficiency in homologous recombination. -
PARP-3 (B-7): Sc-390771
SANTA CRUZ BIOTECHNOLOGY, INC. PARP-3 (B-7): sc-390771 BACKGROUND RECOMMENDED SUPPORT REAGENTS Poly(ADP-ribose) polymerase-3 (PARP-3) is part of the base excision repair To ensure optimal results, the following support reagents are recommended: (BER) pathway, catalyzing the poly(ADP-ribosyl)ation of nuclear proteins. 1) Western Blotting: use m-IgGk BP-HRP: sc-516102 or m-IgGk BP-HRP (Cruz Poly(ADP-ribosyl)ation, a post-translational modification following DNA Marker): sc-516102-CM (dilution range: 1:1000-1:10000), Cruz Marker™ damage, appears as an obligatory step in a detection/signaling pathway Molecular Weight Standards: sc-2035, UltraCruz® Blocking Reagent: leading to the reparation of DNA strand breaks. PARP-3 is a nuclear, DNA- sc-516214 and Western Blotting Luminol Reagent: sc-2048. 2) Immunopre- binding protein, which interacts with PARP-1. PARP-3 is present in actively cipitation: use Protein A/G PLUS-Agarose: sc-2003 (0.5 ml agarose/2.0 ml). dividing tissues with highest levels in the kidney, skeletal muscle, liver, heart 3) Immunofluorescence: use m-IgGk BP-FITC: sc-516140 or m-IgGk BP-PE: and spleen. Human PARP-3 maps to chromosome 3p21.2, a gene region that sc-516141 (dilution range: 1:50-1:200) with UltraCruz® Mounting Medium: undergoes alteration in solid malignant tumors. sc-24941 or UltraCruz® Hard-set Mounting Medium: sc-359850. CHROMOSOMAL LOCATION DATA Genetic locus: PARP3 (human) mapping to 3p21.2; Parp3 (mouse) mapping to 9 F1. AB 132 K – < PARP-3 90 K – 50 K – SOURCE < PARP-3 55 K – PARP-3 (B-7) is a mouse monoclonal antibody raised against amino acids 43 K – 139-219 mapping within an internal region of PARP-3 of human origin. -
A Review of the Recent Advances Made with SIRT6 and Its Implications on Aging Related Processes, Major Human Diseases, and Possible Therapeutic Targets
biomolecules Review A Review of the Recent Advances Made with SIRT6 and its Implications on Aging Related Processes, Major Human Diseases, and Possible Therapeutic Targets Rubayat Islam Khan †, Saif Shahriar Rahman Nirzhor † and Raushanara Akter * Department of Pharmacy, BRAC University, 1212 Dhaka, Bangladesh; [email protected] (R.I.K.); [email protected] (S.S.R.N.) * Correspondence: [email protected]; Tel.: +880-179-8321-273 † These authors contributed equally to this work. Received: 10 June 2018; Accepted: 26 June 2018; Published: 29 June 2018 Abstract: Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide+ (NAD+) dependent enzyme and stress response protein that has sparked the curiosity of many researchers in different branches of the biomedical sciences. A unique member of the known Sirtuin family, SIRT6 has several different functions in multiple different molecular pathways related to DNA repair, glycolysis, gluconeogenesis, tumorigenesis, neurodegeneration, cardiac hypertrophic responses, and more. Only in recent times, however, did the potential usefulness of SIRT6 come to light as we learned more about its biochemical activity, regulation, biological roles, and structure Frye (2000). Even until very recently, SIRT6 was known more for chromatin signaling but, being a nascent topic of study, more information has been ascertained and its potential involvement in major human diseases including diabetes, cancer, neurodegenerative diseases, and heart disease. It is pivotal to explore the mechanistic workings -
DNA Damage Sensitization of Breast Cancer Cells with PARP10/ARTD10 Inhibitor Mikko Hukkanen
Pro gradu DNA damage sensitization of breast cancer cells with PARP10/ARTD10 inhibitor Mikko Hukkanen University of Oulu Faculty of Biochemistry and Molecular Medicine 2019 This thesis was completed at the Faculty of Biochemistry and Molecular Medicine, University of Oulu. Oulu, Finland Supervisors: Professor Lari Lehtiö, Dr. Jarkko Koivunen and MSc Sudarshan Murthy Acknowledgements The work of this thesis was made in Faculty of Biochemistry and Molecular Medicine (FBMM) of University of Oulu. Firstly, I would like to thank Professor Lari Lehtiö for the opportunity working in his group, and the advice I received for my thesis. My gratitude is expressed also to my other supervisors, Jarkko Koivunen, for all the guidance I received in the cell culture, and Sudarshan Murthy, for the guidance to express and purify protein, and to conclude IC50 analysis. I would also thank all the personnel in LL group for all the advice I received in laboratory. I would especially thank Sven Sowa who made the Mantis run for IC50 analysis possible. Abbreviations 5-FU – 5-fluorouracil aa – Aminoacid ADP – Adenosine diphosphate ADPr – ADP-ribosylation AEC – Anion-exchange chromatography AIF – Apoptosis inducing factor AIM – Auto-induction medium Arg – Arginine ART – ADP-ribosyltransferase ARTD – Diphtheria toxin –like ADP-ribosyltransferase Asp – Aspartate BRCA – Breast cancer gene BRCT – BRCA1 C terminus CPT – Camptothecin CRC – Colorectal cancer CRM1 – Chromosome region maintenance 1 Cys – Cysteine DDR – DNA damage response dH2O – Distilled water DMEM – Dulbecco’s -
The PARP Enzyme Family and the Hallmarks of Cancer Part 1. Cell Intrinsic Hallmarks
cancers Review The PARP Enzyme Family and the Hallmarks of Cancer Part 1. Cell Intrinsic Hallmarks Máté A. Demény 1,2,* and László Virág 1,2,* 1 Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary 2 MTA-DE Cell Biology and Signaling Research Group, University of Debrecen, 4032 Debrecen, Hungary * Correspondence: [email protected] (M.A.D.); [email protected] (L.V.) Simple Summary: Poly (ADP-ribose) polymerase (PARP) proteins regulate DNA damage correction, replication, and gene transcription. By controlling pivotal aspects of these processes, PARPs are heavily implicated in cancer development. Inhibitors of PARPs, approved for cancer chemotherapy a few years ago, have achieved great success against tumors of the breast and ovary carrying mutations in the BRCA1/2 genes. The spectrum of the inhibitors is avidly sought to be extended to tumors with different genetic backgrounds and cancers of other origins. This pursuit requires thorough apprehension of PARP-dependent processes affecting cancer development. The hallmarks of cancer are acquired by defining capabilities that differentiate cancer cells from their normal counterparts. Here, in two joint papers, we walk through the connections between these cancer traits and PARP functions. The present review focuses on how PARPs affect the features of cancer that can be attributed to cell-intrinsic changes increasing proliferative potential and survival capabilities. In a kindred paper, we explore the PARP association of cancer hallmarks that derive from tissue-level reorganization in tumors and intercellular interactions of cancer cells. Citation: Demény, M.A.; Virág, L. Abstract: The 17-member poly (ADP-ribose) polymerase enzyme family, also known as the ADP- The PARP Enzyme Family and the ribosyl transferase diphtheria toxin-like (ARTD) enzyme family, contains DNA damage-responsive Hallmarks of Cancer Part 1. -
Elucidating the Tunability of Binding Behavior for the MERS-Cov Macro Domain with NAD Metabolites
ARTICLE https://doi.org/10.1038/s42003-020-01633-6 OPEN Elucidating the tunability of binding behavior for the MERS-CoV macro domain with NAD metabolites Meng-Hsuan Lin1, Chao-Cheng Cho1,2, Yi-Chih Chiu1, Chia-Yu Chien2,3, Yi-Ping Huang4, Chi-Fon Chang4 & ✉ Chun-Hua Hsu 1,2,3 1234567890():,; The macro domain is an ADP-ribose (ADPR) binding module, which is considered to act as a sensor to recognize nicotinamide adenine dinucleotide (NAD) metabolites, including poly ADPR (PAR) and other small molecules. The recognition of macro domains with various ligands is important for a variety of biological functions involved in NAD metabolism, including DNA repair, chromatin remodeling, maintenance of genomic stability, and response to viral infection. Nevertheless, how the macro domain binds to moieties with such structural obstacles using a simple cleft remains a puzzle. We systematically investigated the Middle East respiratory syndrome-coronavirus (MERS-CoV) macro domain for its ligand selectivity and binding properties by structural and biophysical approaches. Of interest, NAD, which is considered not to interact with macro domains, was co-crystallized with the MERS-CoV macro domain. Further studies at physiological temperature revealed that NAD has similar binding ability with ADPR because of the accommodation of the thermal-tunable binding pocket. This study provides the biochemical and structural bases of the detailed ligand- binding mode of the MERS-CoV macro domain. In addition, our observation of enhanced binding affinity of the MERS-CoV macro domain to NAD at physiological temperature highlights the need for further study to reveal the biological functions. 1 Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei 10617, Taiwan. -
P53-Dependent Cell Cycle Checkpoint After DNA Damage and Its
Research and Review Insights Review Article ISSN: 2515-2637 p53-dependent cell cycle checkpoint after DNA damage and its relevance to PARP1 Tadashige Nozaki1* and Mitsuko Masutani2,3 1Department of Pharmacology, Faculty of Dentistry, Osaka Dental University, Japan 2Department of Frontier Life Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Japan 3Division of Cellular Signaling, Laboratory of Collaborative Research, National Cancer Center Research Institute, Japan Abstract The poly(ADP-ribose) polymerase (PARP) inhibitors, including 3-aminobenzamide (3-AB), suppress G1 arrest after DNA damage following gamma-irradiation, suggesting that PARP1, a major PARP family protein, is involved in the induction of G1 arrest. Furthermore, p53 stabilization following gamma-irradiation is not inhibited, but the p53-responsive transient increases of WAF1/CIP1/p21 and MDM2 mRNA have been shown to be suppressed by 3-AB. Therefore, it is suggested that PARP1 participates as a downstream mediator of p53 dependent signal-transduction pathway through the modulation of WAF1/CIP1/p21 and MDM2 mRNA expression. In this review, we discuss p53 cell cycle checkpoint after DNA damage, and its relevance to PARP1. Moreover, the role of PARP1 as a sensor of DNA damage will be proposed. Regulation of p53 and PARP1 activities is an attractive and promising target for the development of clinical treatments for particular diseases. Therefore, it is anticipated that the clinical application of drugs that specifically regulate PARP1 activity will develop in the near future. p53 and G1 checkpoint in cancer DNA damage owing to the abnormal transcriptional regulation by p53 [11,14]. Therefore, it is hypothesized that DNA damage accumulation During the development of cancer, multiple abnormalities occur causes mutated cells to progress into a cancer. -
Parps and ADP-Ribosylation: Recent Advances Linking Molecular Functions to Biological Outcomes
Downloaded from genesdev.cshlp.org on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes Rebecca Gupte,1,2 Ziying Liu,1,2 and W. Lee Kraus1,2 1Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; 2Division of Basic Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA The discovery of poly(ADP-ribose) >50 years ago opened units derived from β-NAD+ to catalyze the ADP-ribosyla- a new field, leading the way for the discovery of the tion reaction. These enzymes include bacterial ADPRTs poly(ADP-ribose) polymerase (PARP) family of enzymes (e.g., cholera toxin and diphtheria toxin) as well as mem- and the ADP-ribosylation reactions that they catalyze. bers of three different protein families in yeast and ani- Although the field was initially focused primarily on the mals: (1) arginine-specific ecto-enzymes (ARTCs), (2) biochemistry and molecular biology of PARP-1 in DNA sirtuins, and (3) PAR polymerases (PARPs) (Hottiger damage detection and repair, the mechanistic and func- et al. 2010). Surprisingly, a recent study showed that the tional understanding of the role of PARPs in different bio- bacterial toxin DarTG can ADP-ribosylate DNA (Jankevi- logical processes has grown considerably of late. This has cius et al. 2016). How this fits into the broader picture of been accompanied by a shift of focus from enzymology to cellular ADP-ribosylation has yet to be determined. -
Different Regulation of PARP1, PARP2, PARP3 and TRPM2 Genes Expression in Acute Myeloid Leukemia Cells
Gil-Kulik et al. BMC Cancer (2020) 20:435 https://doi.org/10.1186/s12885-020-06903-4 RESEARCH ARTICLE Open Access Different regulation of PARP1, PARP2, PARP3 and TRPM2 genes expression in acute myeloid leukemia cells Paulina Gil-Kulik1* , Ewa Dudzińska2,Elżbieta Radzikowska-Büchner3, Joanna Wawer1, Mariusz Jojczuk4, Adam Nogalski4, Genowefa Anna Wawer5, Marcin Feldo6, Wojciech Kocki7, Maria Cioch8†, Anna Bogucka-Kocka9†, Mansur Rahnama10† and Janusz Kocki1† Abstract Background: Acute myeloid leukemia (AML) is a heterogenic lethal disorder characterized by the accumulation of abnormal myeloid progenitor cells in the bone marrow which results in hematopoietic failure. Despite various efforts in detection and treatment, many patients with AML die of this cancer. That is why it is important to develop novel therapeutic options, employing strategic target genes involved in apoptosis and tumor progression. Methods: The aim of the study was to evaluate PARP1, PARP2, PARP3, and TRPM2 gene expression at mRNA level using qPCR method in the cells of hematopoietic system of the bone marrow in patients with acute myeloid leukemia, bone marrow collected from healthy patients, peripheral blood of healthy individuals, and hematopoietic stem cells from the peripheral blood after mobilization. Results: The results found that the bone marrow cells of the patients with acute myeloid leukemia (AML) show overexpression of PARP1 and PARP2 genes and decreased TRPM2 gene expression. In the hematopoietic stem cells derived from the normal marrow and peripheral blood after mobilization, the opposite situation was observed, i.e. TRPM2 gene showed increased expression while PARP1 and PARP2 gene expression was reduced. We observed positive correlations between PARP1, PARP2, PARP3, and TRPM2 genes expression in the group of mature mononuclear cells derived from the peripheral blood and in the group of bone marrow-derived cells.