DOCSLIB.ORG

The Role of ADP-Ribose Metabolism in Metabolic Regulation, Adipose Tissue Differentiation, and Metabolism

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Role of ADP-Ribose Metabolism in Metabolic Regulation, Adipose Tissue Differentiation, and Metabolism Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press SPECIAL SECTION: REVIEW The role of ADP-ribose metabolism in metabolic regulation, adipose tissue differentiation, and metabolism Magdolna Szántó1 and Peter Bai1,2,3 1Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary; 2MTA-DE Lendület Laboratory of Cellular Metabolism, University of Debrecen, Debrecen 4032, Hungary; 3Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary Poly(ADP-ribose) polymerases (PARPs or ARTDs), origi- 2010). Although all PARPs inherited the family name of nally described as DNA repair factors, have metabolic reg- the founding member, PARP-1, the PARP “polyenzymes” ulatory roles. PARP1, PARP2, PARP7, PARP10, and include only PARP-1, PARP-2, and the tankyrases (PARP- PARP14 regulate central and peripheral carbohydrate 5a and PARP-5b) (Gibson and Kraus 2012). Other mem- and lipid metabolism and often channel pathological dis- bers perform only MARylation or oligo(ADP-ribosyl) ruptive metabolic signals. PARP1 and PARP2 are crucial ation, while PARP13 possesses no enzymatic activity for adipocyte differentiation, including the commitment (Hottiger et al. 2010). To our current understanding, the toward white, brown, or beige adipose tissue lineages, as majority of PARP activity is attributed to PARP1 (80%– well as the regulation of lipid accumulation. Through reg- 85%), while the rest is largely attributed to PARP2 (Amé ulating adipocyte function and organismal energy bal- et al. 1999; Schreiber et al. 2002; Szanto et al. 2011). In ance, PARPs play a role in obesity and the consequences most cases, the major acceptor of PAR is PARP1 itself of obesity. These findings can be translated into humans, (termed auto-PARylation); nevertheless, with the use of as evidenced by studies on identical twins and SNPs af- state-of-the-art proteomics a large set of PARylated or fecting PARP activity. ADP-ribosylated proteins were identified and this process is termed trans-PARylation (Chapman et al. 2013; Gibson et al. 2016; Abplanalp et al. 2018; Leslie Pedrioli et al. 2018; Palazzo et al. 2018) (for a comprehensive database of ADP-ribosylated proteins see Vivelo et al. (2017). Brief introduction to ADP-ribose metabolism ADP-ribose unit(s) have rapid turnover and are removed by isoforms of poly(ADP-ribose) glycohydrolase (PARG) The field of poly(ADP-ribose) polymerases (PARPs or (O’Sullivan et al. 2019; Slade 2020), ADP-ribosyl hydro- ARTDs) has come a long way since the discovery of a nu- lase 3 (ARH3) (Oka et al. 2006; Rack et al. 2020), and clear poly(ADP-ribosyl)ating (PARylating) enzyme in ADP-ribosyl protein lyase (Kawaichi et al. 1983). PAR 1963 (Chambon et al. 1963). PARPs now constitute a polymers can be recognized by a set of proteins that con- superfamily of at least 17 members in human that share sequently localize to sites marked by PARP enzymes (Bar- a conserved catalytic domain (Amé et al. 2004; Hottiger kauskaite et al. 2013; Feijs et al. 2013). Karlberg et al. et al. 2010). ADP-ribosylation is a posttranslational (2013) classified enzymes involved in ADPR metabolism modification, during which the ADP-ribosylation en- and recognition as writers, readers, and erasers. zymes cleave NAD+ and attach the resulting ADP-ribose PARP1, PARP2, and PARP3 can be activated by DNA (ADPR) units to acceptor proteins. ADP-ribosylation is re- strand breaks and aberrant DNA forms (Menissier-de ferred to as mono(adp-ribosyl)ation (MARylation), oligo Murcia et al. 1989; Gradwohl et al. 1990; Kutuzov et al. (ADP-ribosyl)ation, or poly(ADP-ribosyl)ation (PARyla- 2013, 2015). Recently, other regulatory routes were de- tion), based on the number of the ADPR units added to scribed. PARP2 is activated by RNA forms (Léger et al. the acceptor protein (Amé et al. 2004; Hottiger et al. 2014); numerous signal transduction pathways, or the stability of PARP proteins were shown to modify the ac- [Keywords: PARP; ARTD; adipocyte; adipogenesis; mitochondria; tivity of PARP isoforms (Gagné et al. 2009; Cantó et al. lipolysis; differentiation; white adipocytes; brown adipocytes; beige 2013). PARPs, especially PARP1 and PARP2, are major adipocytes; stem cell; PARylation; high fat diet; obesity; insulin resistance; NAD+ consumers in the cell (Bai et al. 2011a,b; Mohamed AFLD; NAFLD; atherosclerosis] Corresponding author: [email protected] Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.334284.119. Free- © 2020 Szántó and Bai This article, published in Genes & Development, ly available online through the Genes & Development Open Access is available under a Creative Commons License (Attribution 4.0 Interna- option. tional), as described at http://creativecommons.org/licenses/by/4.0/. GENES & DEVELOPMENT 34:1–20 and Bai; Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/20; www.genesdev.org 1 Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Szántó and Bai et al. 2014) and play a crucial role in regulating NAD+ the central nervous system and the hormonal system, availability and the nonredox functions of NAD+ (often re- which allows the organism to adjust to environmental ferred to as the NAD+ node) (Houtkooper et al. 2010). On and internal metabolic challenges. Such signals are inte- the other hand, PARP activity is dependent on NAD+ lev- grated into the nuclei of the ventromedial hypothalamus, els in cellular compartments and requires a continuous which serve as a central orchestrator and zeitgeber for oth- supply of NAD+. Nicotinamide mononucleotide adenylyl er organs through hypothalamic neurohormonal changes transferase (NMNAT) -1, -2, and -3 are NAD+ synthase en- (Cedernaes et al. 2019). Whole body genetic deletion of zymes that produce NAD+ from nicotinamide mononu- PARP1 alters feeding entrainment in mice and changes cleotide and ATP (Chiarugi et al. 2012; Cohen 2020). spontaneous locomotor activity (Bai et al. 2011b), suggest- Thus, NMNATs can “feed” PARPs with their substrate ing a role for PARP1 in the circadian phase of entrain- and modulate PARP catalytic activity (Berger et al. 2007; ment. PARP1 expression and PARP1 activity show Zhang et al. 2012; Ryu et al. 2018). There are pharmaco- circadian changes in murine models and humans that logical inhibitors available for the study of PARP biology, contribute to circadian entrainment of transcriptional as well as for clinical use. Clinically available PARP inhib- programs in skeletal muscle, the liver, and in the cells of itors include ABT-888 (Veliparib from Abbott/Abbvie) the immune system (Mocchegiani et al. 2003, 2004; Asher rucaparib (Rubraca from Agouron/Pfizer/Clovis), talazo- et al. 2010; Zhao et al. 2015). PARP1 can achieve circadian parib (Talzenna from Lead/Biomarin/Medivation/Pfizer), regulation of gene transcription through the following olaparib (Lynparza from KuDos Pharmaceuticals/Astra- actions: (1) interacting with 11-zinc-finger protein or Zeneca+Merck), and niraparib (Zejula from Merck/ CCCTC-binding factor (CTCF) and converting parts of Tesaro/GSK) (for detailed review, see Slade 2020; Curtin the chromatin to heterochromatin in a time-dependent and Szabo 2013). Although, none of the current PARP in- fashion (Zhao et al. 2015) and (2) interacting with and hibitors seem to discriminate between PARP enzymes ADP-ribosylating Clock protein (Asher et al. 2010). Yet- (Wahlberg et al. 2012), enzyme-specific inhibition of uncovered pathways may also be active. PARP1 activation mono-PARP enzymes may be possible (Venkannagari seems to be vital for sensing or mediating NAD+/NADH et al. 2016; Upton et al. 2017; Holechek et al. 2018). levels to be integrated into cellular energy sensing and sig- PARP enzymes have widespread biological functions naling. Although, the aforementioned pathways were de- ranging from DNA repair and chromatin structure (Javle scribed in nonneuronal models, PARPs are abundantly and Curtin 2011; De Vos et al. 2012; Dantzer and Santoro expressed and active in the nervous system (Komjati 2013), RNA transcription, protein translation, and degra- et al. 2004; Fatokun et al. 2014) and feeding and locomo- dation (Kraus and Hottiger 2013; Bai 2015), cell division, tion behavior changes in the PARP1 knockout mice (Bai tumor biology (Curtin and Szabo 2013), immune process- et al. 2011b), making it likely that these processes are ac- es (Fehr et al. 2020) metabolism, and mitochondrial biol- tive in neurons and other cellular elements of the nervous ogy (Bai and Cantó 2012; Bai et al. 2015), oxidative stress system. It is important to note that disrupting circadian biology, and cell death and differentiation, and aging entrainment increases the risk for obesity and the conse- (Mangerich et al. 2010; Burkle and Virag 2013; Fatokun quences of obesity (Kettner et al. 2015); however, this et al. 2014). In this review, we focus on the metabolic prop- has not been studied in the context of PARP activation. erties of PARP enzymes. PARPs interfere with hormonal signaling at various points. PARPs regulate hormone levels, including intra- muscular androgen production (Marton et al. 2018b). Fast- PARP enzymes in metabolism ing serum insulin levels were lower in PARP2 knockout mice (Bai et al. 2011a), weak PARP inhibitors were shown PARP enzymes impact metabolism at multiple points, ex- to restore insulin expression
Load more

Recommended publications
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • Inhibition of Helicase Activity by a Small Molecule Impairs Werner Syndrome Helicase (WRN) Function in the Cellular Response to DNA Damage Or Replication Stress
    Inhibition of helicase activity by a small molecule impairs Werner syndrome helicase (WRN) function in the cellular response to DNA damage or replication stress Monika Aggarwala, Joshua A. Sommersa, Robert H. Shoemakerb, and Robert M. Brosh, Jr.a,1 aLaboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health Biomedical Research Center, National Institutes of Health, Baltimore, MD 21224; and bScreening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD 21702 Edited by Richard D. Kolodner, Ludwig Institute for Cancer Research, La Jolla, CA, and approved December 15, 2010 (received for review May 11, 2010) Modulation of DNA repair proteins by small molecules has many clinical symptoms of aging at an accelerated rate (7). The attracted great interest. An in vitro helicase activity screen was WRN gene product that is defective in the chromosomal in- used to identify molecules that modulate DNA unwinding by stability disorder has DNA helicase and exonuclease activities Werner syndrome helicase (WRN), mutated in the premature aging and interacts with a number of nuclear proteins to maintain disorder Werner syndrome. A small molecule from the National genomic stability (8). We investigated the hypothesis that a po- Cancer Institute Diversity Set designated NSC 19630 [1-(propox- tent and specific WRN helicase inhibitor could be identified and ymethyl)-maleimide] was identified that inhibited WRN helicase used to inhibit WRN-dependent functions in vivo. Our findings activity but did not affect other DNA helicases [Bloom syndrome provide evidence that a small molecule can modulate in vivo the (BLM), Fanconi anemia group J (FANCJ), RECQ1, RecQ, UvrD, or function of a human helicase in the DNA damage response.
    [Show full text]
  • The PARP Inhibitor Olaparib Modulates the Transcriptional Regulatory Networks of Long Non-Coding Rnas During Vasculogenic Mimicry
    cells Article The PARP Inhibitor Olaparib Modulates the Transcriptional Regulatory Networks of Long Non-Coding RNAs during Vasculogenic Mimicry Mónica Fernández-Cortés , Eduardo Andrés-León and Francisco Javier Oliver * Instituto de Parasitología y Biomedicina López Neyra, CSIC, CIBERONC, 18016 Granada, Spain; [email protected] (M.F.-C.); [email protected] (E.A.-L.) * Correspondence: [email protected] Received: 19 October 2020; Accepted: 11 December 2020; Published: 15 December 2020 Abstract: In highly metastatic tumors, vasculogenic mimicry (VM) involves the acquisition by tumor cells of endothelial-like traits. Poly-(ADP-ribose) polymerase (PARP) inhibitors are currently used against tumors displaying BRCA1/2-dependent deficient homologous recombination, and they may have antimetastatic activity. Long non-coding RNAs (lncRNAs) are emerging as key species-specific regulators of cellular and disease processes. To evaluate the impact of olaparib treatment in the context of non-coding RNA, we have analyzed the expression of lncRNA after performing unbiased whole-transcriptome profiling of human uveal melanoma cells cultured to form VM. RNAseq revealed that the non-coding transcriptomic landscape differed between olaparib-treated and non-treated cells: olaparib significantly modulated the expression of 20 lncRNAs, 11 lncRNAs being upregulated, and 9 downregulated. We subjected the data to different bioinformatics tools and analysis in public databases. We found that copy-number variation alterations in some olaparib-modulated lncRNAs had a statistically significant correlation with alterations in some key tumor suppressor genes. Furthermore, the lncRNAs that were modulated by olaparib appeared to be regulated by common transcription factors: ETS1 had high-score binding sites in the promoters of all olaparib upregulated lncRNAs, while MZF1, RHOXF1 and NR2C2 had high-score binding sites in the promoters of all olaparib downregulated lncRNAs.
    [Show full text]
  • Predictive Biomarkers for Cancer Therapy with PARP Inhibitors
    Oncogene (2014) 33, 3894–3907 & 2014 Macmillan Publishers Limited All rights reserved 0950-9232/14 www.nature.com/onc REVIEW Predictive biomarkers for cancer therapy with PARP inhibitors J Michels1,2,3, I Vitale4,5, M Saparbaev2,3,6, M Castedo1,2,3,11 and G Kroemer1,2,3,7,8,9,10,11 Poly(ADP-ribose) polymerase (PARP) inhibitors have raised high expectations for the treatment of multiple malignancies. PARP inhibitors, which can be used as monotherapies or in combination with DNA-damaging agents, are particularly efficient against tumors with defects in DNA repair mechanisms, in particular the homologous recombination pathway, for instance due to BRCA mutations. Thus, deficient DNA repair provides a framework for the success of PARP inhibitors in medical oncology. Here, we review encouraging results obtained in recent clinical trials investigating the safety and efficacy of PARP inhibitors as anti- cancer agents. We discuss emerging mechanisms of regulation of homologous recombination and how inhibition of DNA repair might be used in cancer therapy. We surmise that the identification of patients that are likely to benefit from PARP inhibition will improve the clinical use of PARP inhibitors in a defined target population. Thus, we will place special emphasis on biomarker discovery. Oncogene (2014) 33, 3894–3907; doi:10.1038/onc.2013.352; published online 16 September 2013 Keywords: PAR; base excision repair; homologous recombination; BRCAness; synthetic lethality INTRODUCTION PARP1 IN PHYSIOLOGICAL AND PATHOLOGICAL RESPONSES The superfamily of
    [Show full text]
  • Predicted Coronavirus Nsp5 Protease Cleavage Sites in The
    bioRxiv preprint doi: https://doi.org/10.1101/2021.06.08.447224; this version posted June 8, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Predicted Coronavirus Nsp5 Protease Cleavage Sites in the 2 Human Proteome: A Resource for SARS-CoV-2 Research 3 Benjamin M. Scott1,2*, Vincent Lacasse3, Ditte G. Blom4, Peter D. Tonner5, Nikolaj S. Blom6 4 1 Associate, Biosystems and Biomaterials Division, National Institute of Standards and Technology, 5 Gaithersburg, Maryland, USA. 6 2 Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland, USA. 7 3 Segal Cancer Proteomics Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, 8 Quebec, Canada 9 4 Department of Applied Mathematics and Computer Science, Technical University of Denmark, Lyngby, 10 Denmark. 11 5 Statistical Engineering Division, National Institute of Standards and Technology, Gaithersburg, Maryland, USA 12 6 Department of Bioengineering, Kongens Lyngby, Technical University of Denmark 13 14 *Corresponding author, [email protected] 15 16 BMS current affiliation: Concordia University, Centre for Applied Synthetic Biology, Montreal, Quebec, Canada 17 18 19 Abstract 20 Background: The coronavirus nonstructural protein 5 (Nsp5) is a cysteine protease required for 21 processing the viral polyprotein and is therefore crucial for viral replication. Nsp5 from several 22 coronaviruses have also been found to cleave host proteins, disrupting molecular pathways 23 involved in innate immunity. Nsp5 from the recently emerged SARS-CoV-2 virus interacts with 24 and can cleave human proteins, which may be relevant to the pathogenesis of COVID-19.
    [Show full text]
  • PARP1-Mediated Necrosis Is Dependent on Parallel JNK and Ca
    ß 2014. Published by The Company of Biologists Ltd | Journal of Cell Science (2014) 127, 4134–4145 doi:10.1242/jcs.128009 RESEARCH ARTICLE PARP1-mediated necrosis is dependent on parallel JNK and Ca2+/calpain pathways Diana L. Douglas1 and Christopher P. Baines1,2,3,* ABSTRACT receptor interacting proteins (RIP, or RIPK) 1 and 3 (Cho et al., 2009; He et al., 2009; Zhang et al., 2009; Li et al., 2012). This Poly(ADP-ribose) polymerase-1 (PARP1) is a nuclear enzyme that complex in turn has been proposed to facilitate necrotic killing can trigger caspase-independent necrosis. Two main mechanisms through a variety of mechanisms, including activation of NADPH for this have been proposed: one involving RIP1 and JNK kinases oxidases (Kim et al., 2007), induction of mitochondrial reactive and mitochondrial permeability transition (MPT), the other involving oxygen species (Irrinki et al., 2011; Vanlangenakker et al., 2011) calpain-mediated activation of Bax and mitochondrial release of and activation of the pseudokinase mixed lineage kinase like apoptosis-inducing factor (AIF). However, whether these two (MLKL) with subsequent activation of the mitochondrial-associated mechanisms represent distinct pathways for PARP1-induced phosphatase PGAM5 (Sun et al., 2012; Wang et al., 2012). necrosis, or whether they are simply different components of the In addition to the necroptosis pathway, another necrotic same pathway has yet to be tested. Mouse embryonic fibroblasts program involving the DNA repair enzyme poly(ADP-ribose) (MEFs) were treated with either N-methyl-N9-nitro-N-nitrosoguanidine polymerase-1 (PARP1) has also emerged. Genotoxic stresses, (MNNG) or b-Lapachone, resulting in PARP1-dependent necrosis.
    [Show full text]