1,365
Views
2
CrossRef citations to date
0
Altmetric
Research Paper

Inhibition of mitochondrial complex III or dihydroorotate dehydrogenase (DHODH) triggers formation of poly(A)+ RNA foci adjacent to nuclear speckles following activation of ATM (ataxia telangiectasia mutated)

& ORCID Icon
Pages 1244-1255 | Received 22 Nov 2021, Accepted 21 Jun 2022, Published online: 22 Nov 2022

References

  • Orphanides G, Reinberg D. A unified theory of gene expression cell. Cell. 2002;108(4):439–451.
  • Millevoi S, Vagner S. Molecular mechanisms of eukaryotic pre-mRNA 3’ end processing regulation. Nucleic Acids Res. 2009;38(9):2757–2774.
  • Bentley DL. Coupling mRNA processing with transcription in time and space. Nat Rev Genet. 2014;15(3):163–175.
  • Kaida D, Motoyoshi H, Tashiro E, et al. Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA Nat. Chem Biol. 2007;3:576–583.
  • Kotake Y, Sagane K, Owa T, et al. Splicing factor SF3b as a target of the antitumor natural product pladienolide. Nat Chem Biol. 2007;3(9):570–575.
  • Hasegawa M, Miura T, Kuzuya K, et al. Identification of SAP155 as the Target of GEX1A (Herboxidienean) Antitumor Natural Product ACS Chem. Biol. 2011;6:229–233.
  • Seiler M, Yoshimi A, Darman R, et al. H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers Nat. Med. 2018;24:497–504.
  • Kahles A, Lehmann KV, Toussaint NC, et al. Comprehensive analysis of alternative splicing across tumors from 8,705 patients. Cancer Cell. 2018;34(2):211–224.
  • Xin P, Xu X, Deng C, et al. The role of JAK/STAT signaling pathway and its inhibitors in diseases. Int Immunopharmacol. 2020;80:106210.
  • Fujiwara N, Yoshikawa M, Yamazaki T, et al. A screening method tuned for mrna processing factors in human cells by evaluation of the luciferase reporter activity and the subcellular distribution of bulk poly(A) + RNA. Biotchnol Biochem. 2010;74(7):1512–1516.
  • Fujita KI, Okamura M, Nishimoto S, et al. Establishment of a Monitoring System to Detect Inhibition of mRNA Processing Biosci. Biotechnol Biochem. 2012;76(6):1248–1251.
  • Kurata M, Fujiwara N, Fujita KI, et al. Food-derived compounds apigenin and luteolin modulate mrna splicing of introns with weak splice sites.iScience. 2019;22:336–352.
  • Evans RD, Guy HI. Mammalian pyrimidine biosynthesis: fresh insights into an ancient pathway. J Biol Chem. 2004;279(32):33035–33038.
  • Alcázar-Fabra M, Navas P, Brea-Calvo G. Coenzyme Q biosynthesis and its role in the respiratory chain structure.Biochimica Biophys Acta Bioenerg2016;1857(8):1073–1078
  • Singh A, Maqbool M, Mobashir M, et al. Dihydroorotate dehydrogenase: a drug target for the development of antimalarials. Eur J Med Chem. 2017;125:640–651.
  • Lolli LM, Sainas S, Pippione CA, et al. Use of human dihydroorotate dehydrogenase (hdhodh) inhibitors in autoimmune diseases and new perspectives in cancer therapy recent pat. Anticancer Drug Discov. 2018;13:86–105.
  • Mao C, Liu X, Zhang Y, et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature. 2021;593(7860):586–590.
  • Sykes BD, Kfoury SY, Mercier EF, et al. Inhibition of dihydroorotate dehydrogenase overcomes differentiation blockade in acute myeloid leukemia. cell. 2016;167:171–186.
  • Yang CF, Gopula B, Liang JJ, et al. Novel AR-12 derivatives, P12-23 and P12-34, inhibit flavivirus replication by blocking host de novo pyrimidine biosynthesis. Emerg Microbes Infect. 2018;7(1):187.
  • Luthra P, Naidoo J, Pietzsch AC, et al. Inhibiting pyrimidine biosynthesis impairs Ebola virus replication through depletion of nucleoside pools and activation of innate immune responses.Antiviral Res. 2018; 158: 288–302.
  • Knight AD, Hejmanowski QA, Dierksheide EJ, et al. Inhibition of herpes simplex virus type 1 by the experimental immunosuppressive agent leflunomide Transplantation. 2001;71:170–174.
  • Fu H, Zhang Z, Dai Y, et al. Brequinar inhibits enterovirus replication by targeting biosynthesis pathway of pyrimidines. Am J Transl Res. 2020;12(12):8247–8255.
  • Park JG, Ávila-Pérez G, Nogales A, et al. Identification and characterization of novel compounds with broad-spectrum antiviral activity against influenza A and. B Viruses J Virol. 2020;94(7):e02149–19.
  • Luban J, Sattler AR, Mühlberger E. The DHODH inhibitor PTC299 arrests SARS-CoV-2 replication and suppresses induction of inflammatory cytokines. Virus Res. 2021;292:198246.
  • Xiong R, Zhang L, Li S. Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2. Protein Cell. 2020;11(10):723–739.
  • Johnson C, Primorac D, McKinstry M, et al. Tracking COL1A1 RNA in osteogenesis imperfecta. splice-defective transcripts initiate transport from the gene but are retained within the SC35 domain. J Cell Biol. 2000;150(3):417–432.
  • Zhang X, Hamblin MH, Yin KJ. The long noncoding RNA Malat1: its physiological and pathophysiological functions. RNA Biol. 2017;14(12):1705–1714.
  • Hirose T, Yamazaki T, Nakagawa S. Molecular anatomy of the architectural NEAT1 noncoding RNA: the domains, interactors, and biogenesis pathway required to build phase-separated nuclear paraspeckles. Wiley Interdiscip Rev RNA. 2019;10(6):e1545.
  • Andrew SG, Phi MD, Zunamys IC, et al. Coilin participates in the suppression of RNA polymerase I in response to cisplatin-induced DNA damage. Mol Biol Cell. 2011;22(7):1070–1079.
  • Martin J, Ajit SD, Shona M, et al. Mitochondrial proton and electron leaks. Essays Biochem. 2010;47:53–67.
  • Lydia GH, John F. Flaherty Atovaquone: a review . Ann Pharmacother. 1993;27(12):1488–1494
  • Anastasia AK, Vladimir VR, Boris VC, et al. Pyrimidine biosynthesis links mitochondrial respiration to the p53 pathway. Proc Natl Acad Sci U S A. 2010;107(29):12828–12833.
  • Bruneau JM, Yea CM, Spinella-Jaegle S, et al. Purification of human dihydro-orotate dehydrogenase and its inhibition by A77 1726, the active metabolite of leflunomide. Biochem J. 1998;336(2):299–303.
  • Sheng Y, Tsutomu K, Qinchang Z, et al. Fluorescence assay of dihydroorotate dehydrogenase that may become a cancer biomarker. Sci Rep. 2017;7:40670.
  • Henghe T, Bruce NC. Understanding the mechanisms of action of methotrexate implications for the treatment of rheumatoid arthritis. Bull Hosp Jt Dis. 2007;65(3):168–173.
  • Deans MR, Morgens WD, Ökesli A, et al. Parallel shRNA and CRISPR-Cas9 screens enable antiviral drug target identification. Nat Chem Biol. 2016;12(5):361–366.
  • Arnould S, Rodier G, Matar G, et al. Checkpoint kinase 1 inhibition sensitises transformed cells to dihydroorotate dehydrogenase inhibition. Oncotarget. 2017;8(56):95206–95222.
  • Lafita-Navarro MC, Venkateswaran N, Kilgore JA, et al. Inhibition of the de novo pyrimidine biosynthesis pathway limits ribosomal RNA transcription causing nucleolar stress in glioblastoma cells. PLoS Genet. 2020;16(11):e1009117.
  • Hubackova S, Davidova E, Boukalova S, et al. Replication and ribosomal stress induced by targeting pyrimidine synthesis and cellular checkpoints suppress p53-deficient tumors. Cell Death Dis. 2020;11(2):110.
  • Berger DN, Stanley FKT, Moore S, et al. ATM-dependent pathways of chromatin remodelling and oxidative DNA damage responses. Philos Trans R Soc Lond B Biol Sci. 2017;372(1731):20160283.
  • Ladds MJGW, van Leeuwen IMM, Drummond CJ, et al. A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage. Nat Commun. 2018;9(1):1107.
  • Rainey MD, Charlton ME, Stanton RV, et al. Transient inhibition of ATM kinase is sufficient to enhance cellular sensitivity to ionizing radiation. Cancer Res. 2008;68(18):7466–7474.
  • Zhang A, Lyu YL, Lin CP, et al. A protease pathway for the repair of topoisomerase II-DNA covalent complexes. J Biol Chem. 2006;281(47):35997–36003.
  • Tanaka T, Halicka HD, Traganos F, et al. Induction of ATM activation, histone H2AX phosphorylation and apoptosis by etoposide: relation to cell cycle phase. Cell cycle. 2007;6(3):371–376.
  • Kurz EU, Lees-Miller SP. DNA damage-induced activation of ATM and ATM-dependent signaling pathways.DNA Repair (Amst). 2004;3(8–9):889–900.
  • Fokas E, Prevo R, Pollard JR, et al. Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell Death Dis. 2012;3(12):e441.
  • Sharma A, Singh K, Almasan A. Histone H2AX phosphorylation: a marker for DNA damage Methods. Mol Biol. 2012;920:613–626.
  • Santoriello C, Sporrij A, Yang S, et al. RNA helicase DDX21 mediates nucleotide stress responses in neural crest and melanoma cells. Nat Cell Biol. 2020;22(4):372–379.
  • Jia W, Yao Z, Zhao J, et al. New perspectives of physiological and pathological functions of nucleolin (NCL. Life Sci. 2017;186:1–10.
  • Grzanka M, Piekiełko-Witkowska A. The Role of TCOF1 Gene in Health and Disease. Int J Mol Sci. 2021;22(5):2482.
  • Korsholm LM, Gál Z, Lin L, et al. Double-strand breaks in ribosomal RNA genes activate a distinct signaling and chromatin response to facilitate nucleolar restructuring and repair. Nucleic Acids Res. 2019 Sep 5 47(15):8019–8035.
  • Calo E, Gu B, Bowen ME, et al. Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders. Nature. 2018;554(7690):112–117.
  • Inoue A, Tsugawa K, Tokunaga K, et al. S1-1 nuclear domains: characterization and dynamics as a function of transcriptional activity. Biol Cell. 2008;100(9):523–535.
  • Hsiang YH, Hertzberg R, Hecht S, et al. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem. 1985;260(27):14873–14878.
  • Diouf B, Lin W, Goktug A, et al. Alteration of RNA splicing by small-molecule inhibitors of the interaction between NHP2L1 and U4. SLAS Discov. 2018;23(2):164–173.
  • Francis LK, Alsayed Y, Leleu X, et al. Combination mammalian target of rapamycin inhibitor rapamycin and HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin has synergistic activity in multiple myeloma. Clin Cancer Res. 2006;12(22):6826–6835.
  • Ferraldeschi R, Welti J, Powers MV, et al. Second-generation hsp90 inhibitor onalespib blocks mrna splicing of androgen receptor variant 7 in prostate cancer cells. Cancer Res. 2016;76(9):2731–2742.
  • Lindell TJ, Weinberg F, Morris PW, et al. Specific inhibition of nuclear RNA polymerase II by alpha-amanitin. Science. 1970;170(3956):447–449.
  • Carmo-Fonseca M, Pepperkok R, Carvalho MT, et al. Transcription-dependent colocalization of the U1, U2, U4/U6, and U5 snRNPs in coiled bodies. J Cell Biol. 1992;117(1):1–14.
  • Wang P, Lou PJ, Leu S, et al. Modulation of alternative pre-mRNA splicing in vivo by pinin. Biochem Biophys Res Commun. 2002;294(2):448–455.
  • Spector DL. Nuclear organization and gene expression. Exp Cell Res. 1996;229(2):189–197.
  • Dabo S, Meurs EF. dsRNA-dependent protein kinase PKR and its role in stress, signaling and HCV infection. Viruses. 2012;4(11):2598–2635.
  • Ilan L, Osman F, Namer LS, et al. PKR activation and eIF2α phosphorylation mediate human globin mRNA splicing at spliceosome assembly. Cell Res. 2017;27(5):688–704.
  • Murphy T, Yee KWL. Cytarabine and daunorubicin for the treatment of acute myeloid leukemia. Expert Opin Pharmacother. 2017;18(16):1765–1780.
  • Wander DPA, van der Zanden SY, van der Marel GA, et al. Doxorubicin and Aclarubicin: shuffling Anthracycline Glycans for Improved Anticancer Agents. J Med Chem. 2020;63(21):12814–12829.
  • van der Zanden Sy, Qiao X, Neefjes J. New insights into the activities and toxicities of the old anticancer drug doxorubicin. FEBS J. 2021;288(21):6095–6111.
  • Lee JS, Lin YY, Wang TS, et al. Antitumorigenic Effects of ZAKβ, an Alternative Splicing Isoform of ZAK. Chin J Physiol. 2018;61(1):25–34.
  • Jiang D, Lynch C, Medeiros BC, et al. Identification of doxorubicin as an inhibitor of the IRE1α-XBP1 axis of the unfolded protein response. Sci Rep. 2016;6(1):33353.
  • Chatham JC, Young ME, Zhang J. Role of O-linked N-acetylglucosamine (O-GlcNAc) modification of proteins in diabetic cardiovascular complications. Curr Opin Pharmacol. 2021;57:1–12.
  • Bennett EP, Mandel U, Clausen H, et al. Control of mucin-type O-glycosylation: a classification of the polypeptide GalNAc-transferase gene family. Glycobiology. 2012;22(6):736–756.
  • Chen J, Yang S. Catalytic mechanism of UDP-glucose dehydrogenase. Biochem Soc Trans. 2019;47(3):945–955.
  • Lewis BA, Burlingame AL, Myers SA. Human RNA Polymerase II Promoter Recruitment in Vitro Is Regulated by O-Linked N-Acetylglucosaminyltransferase (OGT). J Biol Chem. 2016;291(27):14056–14061.
  • Echizenya S, Ishii Y, Kitazawa S, et al. Discovery of a new pyrimidine synthesis inhibitor eradicating glioblastoma-initiating cells. Neuro Oncol. 2020;22(2):229–239.
  • Madak JT, Bankhead A 3rd, Cuthbertson CR, et al. Revisiting the role of dihydroorotate dehydrogenase as a therapeutic target for cancer. Pharmacol Ther. 2019;195:111–131.
  • Zhou Y, Tao L, Zhou X, et al. DHODH and cancer: promising prospects to be explored. Cancer Metab. 2021;9(1):22.
  • Bar-Or A, Pachner A, Menguy-Vacheron F, et al. Teriflunomide and its mechanism of action in multiple sclerosis. Drugs. 2014;74(6):659–674.
  • Alamri RD, Elmeligy MA, Albalawi GA, et al. Leflunomide an immunomodulator with antineoplastic and antiviral potentials but drug-induced liver injury: a comprehensive review. Int Immunopharmacol. 2021;93:107398.
  • Ilik İA, Malszycki M, Lübke AK, et al. SON and SRRM2 are essential for nuclear speckle formation. Elife. 2020;9:e60579.