248
Views
0
CrossRef citations to date
0
Altmetric
Review

Ribosomopathies and cancer: pharmacological implications

, , , , ORCID Icon, ORCID Icon, & ORCID Icon show all
Pages 729-746 | Received 03 Jun 2021, Accepted 01 Jul 2022, Published online: 15 Jul 2022

References

  • Palade GE, Porter KR. Studies on the endoplasmic reticulum. I. Its identification in cells in situ. J Exp Med. 1954;100:641–656.
  • Nürenberg-Goloub E, Tampé R. Ribosome recycling in mRNA translation, quality control, and homeostasis. Biol Chem. 2019;401(1):47–61.
  • Kampen KR, Sulima SO, Vereecke S, et al., Hallmarks of ribosomopathies. Nucleic Acids Res. 2020;48(3): 1013–1028.
  • Hellen CUT. Translation termination and ribosome recycling in eukaryotes. Cold Spring Harb Perspect Biol. 2018;10:a032656.
  • Shirokikh NE, Preiss T. Translation initiation by cap- dependent ribosome recruitment: recent insights and open questions. Wiley Interdiscip Rev RNA. 2018;9:e1473.
  • Stein KC, Frydman J. The stop-and-go traffic regulating protein biogenesis: how translation kinetics controls proteostasis. J Biol Chem. 2019;294:2076–2084.
  • McStay B. Nucleolar organizer regions: genomic ‘dark matter’ requiring illumination. Genes Dev. 2016;30:1598–1610.
  • Henras AK, Plisson-Chastang C, O’Donohue MF, et al. An overview of preribosomal RNA processing in eukaryotes. Wiley Interdiscip Rev RNA. 2015;6:225–242.
  • Sørensen PD, Frederiksen S. Characterization of human 5S rRNA genes. Nucleic Acids Res. 1991;19:4147–4151.
  • Wang W, Nag S, Zhang X, et al. Ribosomal proteins and human diseases: pathogenesis, molecular mechanisms, and therapeutic implications. Med Res Rev. 2015;35:225–285.
  • Fromont-Racine M, Senger B, Saveanu C, et al. Ribosome assembly in eukaryotes. Gene. 2003;313:17–42.
  • Golomb L, Volarevic S, Oren M. p53 and ribosome biogenesis stress: the essentials. FEBS Lett. 2014;588:2571–2579.
  • Parks MM, Kurylo CM, Dass RA, et al. Variant ribosomal RNA alleles are conserved and exhibit tissue-specific expression. Sci Adv. 2018;4:eaao0665.
  • Polikanov YS, Melnikov SV, Soll D, et al. Structural insights into the role of rRNA modifications in protein synthesis and ribosome assembly. Nat Struct Mol Biol. 2015;22:342–344.
  • Sharma S, Lafontaine DLJ. ‘View from a bridge’: a new perspective on eukaryotic rRNA base modification. Trends Biochem Sci. 2015;40:560–575.
  • Natchiar SK, Myasnikov AG, Kratzat H, et al. Visualization of chemical modifications in the human 80S ribosome structure. Nature. 2017;551:472–477.
  • Roundtree IA, Evans ME, Pan T, et al. Dynamic RNA modifications in gene expression regulation. Cell. 2017;169:1187–1200.
  • Schosserer M, Minois N, Angerer TB, et al. Methylation of ribosomal RNA by NSUN5 is a conserved mechanism modulating organismal lifespan. Nat Commun. 2015;6:6158.
  • Sloan KE, Warda AS, Sharma S, et al. Tuning the ribosome: the influence of rRNA modification on eukaryotic ribosome biogenesis and function. RNA Biol. 2017;14:1138–1152.
  • Sharma S, Hartmann JD, Watzinger P, et al. A single N1-methyladenosine on the large ribosomal subunit rRNA impacts locally its structure and the translation of key metabolic enzymes. Sci Rep. 2018;8:11904.
  • Bellodi C, Kopmar N, Ruggero D. Deregulation of oncogene-induced senescence and p53 translational control in X-linked dyskeratosis congenita. EMBO J. 2010;29:1865–1876.
  • Truitt ML, Ruggero D. New frontiers in translational control of the cancer genome. Nat Rev Cancer. 2017;17:332.
  • Doll A, Grzeschik KH. Characterization of two novel genes, WBSCR20 and WBSCR22, deleted in Williams-Beuren syndrome. Cytogenet Cell Genet. 2001;95:20–27.
  • Armistead J, Khatkar S, Meyer B, et al. Mutation of a gene essential for ribosome biogenesis, EMG1, causes Bowen-Conradi syndrome. Am J Hum Genet. 2009;84:728–739.
  • Montanaro L, Treré D, Derenzini M. Nucleolus, ribosomes, and cancer. Am J Pathol. 2008;173:301–310.
  • Narla A, Ebert BL. Ribosomopathies: human disorders of ribosome dysfunction. Blood. 2010;115:3196–3205.
  • Armistead J, Triggs-Raine B. Diverse diseases from a ubiquitous process: the ribosomopathy paradox. FEBS Lett. 2014;588:1491–1500.
  • Danilova N, Gazda HT. Ribosomopathies: how a common root can cause a tree of pathologies. Dis Model Mech. 2015;8:1013–1026.
  • Wilson DN, Doudna Cate JH. The structure and function of the eukaryotic ribosome. Cold Spring Harb Perspect Biol. 2012;4(5):a011536.
  • Doudna JA, Rath VL. Structure and function of the eukaryotic ribosome: the next frontier. Cell. 2002;109(2):153–156.
  • Fatica A, Tollervey D. Making ribosomes. Curr Opin Cell Biol. 2002;14(3):313–318.
  • O’Donohue MF, Choesmel V, Faubladier M, et al. Functional dichotomy of ribosomal proteins during the synthesis of mammalian 40S ribosomal subunits. J Cell Biol. 2010;190(5):853–866.
  • Rahhal R, Seto E. Emerging roles of histone modifications and HDACs in RNA splicing. Nucleic Acids Res. 2019;47(10):4911–4926.
  • Smith MC, Mader MM, Cook JA, et al. Characterization of LY3023414, a novel PI3K/mTOR dual inhibitor eliciting transient target modulation to impede tumor growth. Mol Cancer Ther. 2016;15:2344–2356.
  • Russell J, Zomerdijk JC. RNA-polymerase-I-directed rDNA transcription, life and works. Trends Biochem Sci. 2005;30:87–96.
  • Albert B, Perez-Fernandez J, Léger-Silvestre I, et al. Regulation of ribosomal RNA production by RNA polymerase I: does elongation come first? Genet Res Int. 2012;2012:276948.
  • Greber BJ, Gerhardy S, Leitner A, et al. Insertion of the biogenesis factor rei1 probes the ribosomal tunnel during 60S maturation. Cell. 2016;164:1–12.
  • Zhu J, Blenis J, Yuan J. Activation of PI3K/Akt and MAPK pathways regulates myc-mediated transcription by phosphorylating and promoting the degradation of mad1. Proc Natl Acad Sci USA. 2008;105:6584–6589.
  • Mendoza MC, Er EE, The Ras-ERK BJ. and PI3KmTOR pathways: cross-talk and compensation. Trends Biochem Sci. 2011;36:320–328.
  • Mayer C, Grummt I. Ribosome biogenesis and cell growth: mTOR coordinates transcription by all three classes of nuclear RNA polymerases. Oncogene. 2006;25:6384–6391.
  • Woiwode A, Johnson SA, Zhong S, et al. PTEN represses RNA polymerase III-dependent transcription by targeting the TFIIIB complex. Mol Cell Biol. 2008;28:4204–4214.
  • Kantidakis T, Ramsbottom BA, Birch JL, et al. mTOR associates with TFIIIC, is found at tRNA and 5S rRNA genes, and targets their repressor Maf1. Proc Natl Acad Sci USA. 2010;107:11823–11828.
  • Watkins NJ, Bohnsack MT. The box C/D and H/ACA snoRNPs: key players in the modification, processing and the dynamic folding of ribosomal RNA. Wiley Interdiscip Rev RNA. 2012;3:397–414.
  • Cong R, Das S, Ugrinova I, et al. Interaction of nucleolin with ribosomal RNA genes and its role in RNA polymerase I transcription. Nucleic Acids Res. 2012;40:9441–9454.
  • Ginisty H, Amalric F, Bouvet P. Nucleolin functions in the first step of ribosomal RNA processing. EMBO J. 1998;17:1476–1486.
  • Roger B, Moisand A, Amalric F, et al. Nucleolin provides a link between RNA polymerase I transcription and pre-ribosome assembly. Chromosoma. 2003;111:399–407.
  • Ginisty H, Serin G, Ghisolfi-Nieto L, et al. Interaction of nucleolin with an evolutionarily conserved pre-ribosomal RNA sequence is required for the assembly of the primary processing complex. J Biol Chem. 2000;275:18845–18850.
  • Murano K, Okuwaki M, Hisaoka M, et al. Transcription regulation of the rRNA gene by a multifunctional nucleolar protein, B23/nucleophosmin, through its histone chaperone activity. Mol Cell Biol. 2008;28:3114–3126.
  • Savkur RS, Olson MO. Preferential cleavage in preribosomal RNA byprotein B23 endoribonuclease. Nucleic Acids Res. 1998;26:4508–4515.
  • Yu Y, Maggi LB Jr, Brady SN, et al. Nucleophosmin is essential for ribosomal protein L5 nuclear export. Mol Cell Biol. 2006;26:3798–3809.
  • LBJr M, Kuchenruether M, Dadey DY, et al. Nucleophosmin serves as a rate-limiting nuclear export chaperone for the mammalian ribosome. Mol Cell Biol. 2008;28:7050–7065.
  • Box JK, Paquet N, Adams MN, et al. Nucleophosmin: from structure and function to disease development. BMC Mol Biol. 2016;17:19.
  • Itahana K, Bhat KP, Jin A, et al. Tumor suppressor ARF degrades B23, a nucleolar protein involved in ribosome biogenesis and cell proliferation. Mol Cell. 2003;12:1151–1164.
  • Kerr LE, Birse-Archbold JL, Short DM, et al. Nucleophosmin is a novel Bax chaperone that regulates apoptotic cell death. Oncogene. 2007;26:2554–2562.
  • Henras AK, Soudet J, Gérus M, et al. The post-transcriptional steps of eukaryotic ribosome biogenesis. Cell Mol Life Sci. 2008;65:2334–2359.
  • Shenoy N, Kessel R, Bhagat TD, et al. Alterations in the ribosomal machinery in cancer and hematologic disorders. J Hematol Oncol. 2012;5:32.
  • Boon K, Caron HN, van Asperen R, et al. N-myc enhances the expression of a large set of genes functioning in ribosome biogenesis and protein synthesis. EMBO J. 2001;20(6):1383–1393.
  • Ruggero D, Pandolfi PP. Does the ribosome translate cancer? Nat Rev Cancer. 2003;3(3):179–192.
  • Ferreira R, JSJr S, Panov KI, et al. Targeting the RNA polymerase I transcription for cancer therapy comes of age. Cells. 2020;9:266.
  • Bywater MJ, Poortinga G, Sanij E, et al. Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. Cancer Cell. 2012;22:51–65.
  • Wei T, Najmi SM, Liu H, et al. Small-molecule targeting of RNA polymerase I activates a conserved transcription elongation checkpoint. Cell Rep. 2018;23:404–414.
  • Kusnadi EP, Trigos AS, Cullinane C, et al., Reprogrammed mRNA translation drives metabolic response to therapeutic targeting of ribosome biogenesis. EMBO J. 39(21): e105111. 2020.
  • Xu H, Di Antonio M, McKinney S, et al. CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours. Nat Commun. 2017;8:14432.
  • Drygin D, Lin A, Bliesath J, et al. Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth. Cancer Res. 2011;71:1418–1430.
  • Peltonen K, Colis L, Liu H, et al. A targeting modality for destruction of RNA polymerase I that possesses anticancer activity. Cancer Cell. 2014;25:77–90.
  • Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res. 2003;23:363–398.
  • Bharti AC, Donato N, Singh S, et al. Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and IkappaBalpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. Blood. 2003;101:1053–1062.
  • Jutooru I, Chadalapaka G, Lei P, et al. Inhibition of NF kappa B and pancreatic cancer cell and tumor growth by curcumin is dependent on specificity protein down-regulation. J Biol Chem. 2010;285:25332–25344.
  • Kawamori T, Lubet R, Steele VE, et al. Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory agent, during the promotion/progression stages of colon cancer. Cancer Res. 1999;59:597–601.
  • Chen YR, Tan TH. Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by curcumin. Oncogene. 1998;17:173–178.
  • Sun XD, Liu XE, Huang DS. Curcumin induces apoptosis of triple-negative breast cancer cells by inhibition of EGFR expression. Mol Med Rep. 2012;6:1267–1270.
  • Yun JH, Park YG, Lee KM, et al. Curcumin induces apoptotic cell death via Oct4 inhibition and GSK-3beta activation in NCCIT cells. Mol Nutr Food Res. 2015;59:1053–1062.
  • Xu Y, Wu Y, Wang L, et al. Identification of curcumin as a novel natural inhibitor of rDNA transcription. Cell Cycle. 2020;19(23):3362–3374.
  • Andrews WJ, Panova T, Normand C, et al. Old drug, new target: ellipticines selectively inhibit RNA polymerase I transcription. J Biol Chem. 2013;288:4567–4582.
  • Brown RV, Danford FL, Gokhale V, et al. Demonstration that drug-targeted down-regulation of MYC in non-Hodgkins lymphoma is directly mediated through the promoter G-quadruplex. J Biol Chem. 2011;286:41018–41027.
  • Likovsky Z, Peterka M, Peterkova R. Drug-induced changes of rRNA biosynthesis – a marker of toxic damage to embryonal cell population. Funct Dev Morphol. 1993;3:3–9.
  • Rey JP, Scott R, Muller H. Induction and removal of interstrand crosslinks in the ribosomal RNA genes of lymphoblastoid cell lines from patients with Fanconi anemia. Mutat Res. 1993;289:171–180.
  • Mathijssen RH, Loos WJ, Verweij J, et al. Pharmacology of topoisomerase I inhibitors irinotecan (CPT-11) and topotecan. Curr Cancer Drug Targets. 2002;2(2):103–123.
  • Burger K, Mühl B, Harasim T, et al. Chemotherapeutic drugs inhibit ribosome biogenesis at various levels. J Biol Chem. 2010;285:12416–12425.
  • Gilder AS, Do PM, Carrero ZI, et al. Coilin participates in the suppression of RNA polymerase I in response to cisplatin-induced DNA damage. Mol Biol Cell. 2011;22:1070–1079.
  • Haaf T, Ward DC. Inhibition of RNA polymerase II transcription causes chromatin decondensation, loss of nucleolar structure, and dispersion of chromosomal domains. Exp Cell Res. 1996;224:163–173.
  • Bruno PM, Liu Y, Park GY, et al. A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress. Nat Med. 2017;23:461–471.
  • Sutton EC, McDevitt CE, Prochnau JY, et al. Nucleolar stress induction by oxaliplatin and derivatives. J Am Chem Soc. 2019;141(46):18411–18415.
  • Peyroche G, Milkereit P, Bischler N, et al. The recruitment of RNA polymerase I on rDNA is mediated by the interaction of the A43 subunit with Rrn3. EMBO J. 2000;19:5473–5482.
  • Miller G, Panov KI, Friedrich JK, et al. hRRN3 is essential in the SL1-mediated recruitment of RNA polymerase I to rRNA gene promoters. EMBO J. 2001;20:1373–1382.
  • Milkereit P, Tschochner H. A specialized form of RNA polymerase I, essential for initiation and growth-dependent regulation of rRNA synthesis, is disrupted during transcription. EMBO J. 1998;17:3692–3703.
  • Gnanasundram SV, Pyndiah S, Daskalogianni C, et al. PI3K_ activates E2F1 synthesis in response to mRNA translation stress. Nat Commun. 2017;8:2103.
  • Rothblum K, Hu Q, Penrod Y, et al. Selective inhibition of rDNA transcription by a small- molecule peptide that targets the interface between RNA polymerase I and Rrn3. Mol Cancer Res. 2014;12:1586–1596.
  • Pertschy B, Zisser G, Schein H, et al. Diazaborine treatment of yeast cells inhibits maturation of the 60s ribosomal subunit. Mol Cell Biol. 2004;24:6476–6487.
  • Kawashima SA, Chen Z, Aoi Y, et al. Potent, reversible, and specific chemical inhibitors of eukaryotic ribosome biogenesis. Cell. 2016;167:512–524.
  • Kofler L, Prattes M, Bergler H. Inhibiting eukaryotic ribosome biogenesis: mining new tools for basic research and medical applications. Microb Cell. 2019;6(10):491–493.
  • Awad D, Prattes M, Kofler L, et al. Inhibiting eukaryotic ribosome biogenesis. BMC Biol. 2019;17:46.
  • Shelton J, Lu X, Hollenbaugh JA, et al. Metabolism, biochemical actions, and chemical synthesis of anticancer nucleosides, nucleotides, and base analogs. Chem Rev. 2016;116(23):14379–14455.
  • Caro-Vegas C, Bailey A, Bigi R, et al. Targeting mTOR with MLN0128 overcomes rapamycin and chemoresistant primary effusion lymphoma. MBio. 2019;10:e02871–18.
  • Kwon Y, Cha J, Chiang J, et al. A chemogenomic approach to understand the antifungal action of Lichen derived vulpinic acid. J Appl Microbiol. 2016;121(6):1580–1591.
  • Rajagopalan PTR, Zhang Z, McCourt L, et al. Interaction of dihydrofolate reductase with methotrexate: ensemble and single-molecule kinetics. Proc Natl Acad Sci. 2002;99(21):13481–13486.
  • Albrecht LV, Bui MH, Robertis EMD. Canonical Wnt is inhibited by targeting one-carbon metabolism through methotrexate or methionine deprivation. Proc Natl Acad Sci. 2019;116(8):2987–2995.
  • Bidou L, Allamand V, Rousset JP, et al. Sense from nonsense: therapies for premature stop codon diseases. Trends Mol Med. 2012;18:679–688.
  • Shi Y, Zhai H, Wang X, et al. Ribosomal proteins S13 and L23 promote multidrug resistance in gastric cancer cells by suppressing drug-induced apoptosis. Exp Cell Res. 2004;296(2):337–346.
  • Speth J, Shi Y, Pan Y, et al. Regulation of multidrug resistance by ribosomal protein l6 in gastric cancer cells. Cancer Biol Ther. 2005;4(2):242–247.
  • Huang XP, Zhao CX, Li QJ, et al. Alteration of RPL14 in squamous cell carcinomas and preneoplastic lesions of the esophagus. Gene. 2006;366(1):161–168.
  • Kim JH, You KR, Kim IH, et al. Over-expression of the ribosomal protein L36a gene is associated with cellular proliferation in hepatocellular carcinoma. Hepatology. 2004;39(1):129–138.
  • Wang H, Zhao LN, Li KZ, et al. Overexpression of ribosomal protein L15 is associated with cell proliferation in gastric cancer. BMC Cancer. 2006;6:91.
  • Gou Y, Shi Y, Zhang Y, et al. Ribosomal protein L6 promotes growth and cell cycle progression through upregulating cyclin E in gastric cancer cells. Biochem Biophys Res Commun. 2010;393(4):788–793.
  • Kobayashi T, Sasaki Y, Oshima Y, et al. Activation of the ribosomal protein L13 gene in human gastrointestinal cancer. Int J Mol Med. 2006;18(1):161–170.
  • Pogue-Geile K, Geiser JR, Shu M, et al. Ribosomal protein genes are overexpressed in colorectal cancer: isolation of a cDNA clone encoding the human S3 ribosomal protein. Mol Cell Biol. 1991;11(8):3842–3849.
  • Kasai H, Nadano D, Hidaka E, et al. Differential expression of ribosomal proteins in human normal and neoplastic colorectum. J Histochem Cytochem. 2003;51(5):567–574.
  • Ohkia A, Hu Y, Wang M, et al. Evidence for prostate cancer-associated diagnostic marker-1: immunohistochemistry and in situ hybridization studies. Clin Cancer Res. 2004;10(7):2452–2458.
  • Wang M, Hu YJ, Stearns ME. RPS2: a novel therapeutic target in prostate cancer. J Exp Clin Cancer Res. 2009;28:6.
  • Wang Q, Yang C, Zhou J, et al. Cloning and characterization of full-length human ribosomal protein L15 cDNA which was overexpressed in esophageal cancer. Gene. 2001;263(1–2):205–209.
  • Kim SH, Jang YH, Chau GC, et al. Prognostic significance and function of phosphorylated ribosomal protein S6 in esophageal squamous cell carcinoma. Mod Pathol. 2013;26(3):327–335.
  • Yang M, Sun H, Wang H, et al. Down-regulation of ribosomal protein L22 in non-small cell lung cancer. Med Oncol. 2013;30(3):646.
  • McDonald JM, Pelloski CE, Ledoux A, et al. Elevated phospho-S6 expression is associated with metastasis in adenocarcinoma of the lung. Clin Cancer Res. 2008;14(23):7832–7837.
  • Wang S, Huang J, He J, et al. RPL41, a small ribosomal peptide deregulated in tumors, is essential for mitosis and centrosome integrity. Neoplasia. 2010;12(3):284–293.
  • Zheng SE, Yao Y, Dong Y, et al. Down-regulation of ribosomal protein L7A in human osteosarcoma. J Cancer Res Clin Oncol. 2009;135(8):1025–1031.
  • Hagner PR, Mazan-Mamczarz K, Dai B, et al. Ribosomal protein S6 is highly expressed in non-Hodgkin lymphoma and associates with mRNA containing a 5’ terminal oligopyrimidine tract. Oncogene. 2011;30(13):1531–1541.
  • Wu LY, Li X, Xu F, et al. Over-expression of RPL23 in myelodysplastic syndromes is associated with apoptosis resistance of CD34(+) cells and predicts poor prognosis and distinct response to CHG chemotherapy or decitabine. Ann Hematol. 2012;91(10):1547–1554.
  • Tsofack SP, Meunier L, Sanchez L, et al. Low expression of the X-linked ribosomal protein S4 in human serous epithelial ovarian cancer is associated with a poor prognosis. BMC Cancer. 2013;13:303.
  • Simsek D, Barna M. An emerging role for the ribosome as a nexus for post-translational modifications. Curr Opin Cell Biol. 2017;45:92–101.
  • Emmott E, Jovanovic M, Ribosome Stoichiometry: SN. From Form to Function. Trends Biochem Sci. 2019;44:95–109.
  • Li C, Ge M, Yin Y, et al. Silencing expression of ribosomal protein L26 and L29 by RNA interfering inhibits proliferation of human pancreatic cancer PANC-1 cells. Mol Cell Biochem. 2012;370(1–2):127–139.
  • Wu Q, Gou Y, Wang Q, et al. Downregulation of RPL6 by siRNA inhibits proliferation and cell cycle progression of human gastric cancer cell lines. PLoS One. 2011;6(10):e26401.
  • Bee A, Brewer D, Beesley C, et al. siRNA knockdown of ribosomal protein gene RPL19 abrogates the aggressive phenotype of human prostate cancer. PLoS One. 2011;6(7):e22672.
  • Hollstein M, Sidransky D, Vogelstein B, et al. p53 mutations in human cancers. Science. 1991;253:49–53.
  • Bursac S, Brdovcak MC, Donati G, et al. Activation of the tumor suppressor p53 upon impairment of ribosome biogenesis. Biochim Biophys Acta-Mol Basis Dis. 2014; 1842: 817–830.
  • James A, Wang Y, Raje H, et al. Nucleolar stress with and without p53. Nucleus. 2014;5:402–426.
  • Orsolic I, Jurada D, Pullen N, et al. The relationship between the nucleolus and cancer: current evidence and emerging paradigms. Semin Cancer Biol. 2016;37(38):36–50.
  • Holmberg Olausson K, Nistér M, Lindström M, et al. p53 -dependent and -independent nucleolar stress responses. Cells. 2012;1:774–798.
  • Kappel L, Loibl M, Zisser G, et al. Rlp24 activates the AAA-ATPase Drg1 to initiate cytoplasmic pre-60S maturation. J Cell Biol. 2012;199:771–782.
  • Bassler J, Kallas M, Pertschy B, et al. The AAA-ATPase Rea1 drives removal of biogenesis factors during multiple stages of 60S ribosome assembly. Mol Cell. 2010;38:712–721.
  • Anderson DJ, Le Moigne R, Djakovic S, et al. Targeting the AAA ATPase p97 as an approach to treat cancer through disruption of protein homeostasis. Cancer Cell. 2015;28(5):653–665.
  • Firestone AJ, Weinger JS, Maldonado M, et al. Small-molecule inhibitors of the AAA+ ATPase motor cytoplasmic dynein. Nature. 2012;484(7392):125–129.
  • Lindstrom MS. NPM1/B23: a multifunctional chaperone in ribosome biogenesis and chromatin remodeling. Biochem Res Int. 2011;2011:195209.
  • Qi W, Shakalya K, Stejskal A, et al. NSC348884, a nucleophosmin inhibitor disrupts oligomer formation and induces apoptosis in human cancer cells. Oncogene. 2008;27:4210–4220.
  • Wulff JE, Siegrist R, Myers AG. The natural product avrainvillamide binds to the oncoprotein nucleophosmin. J Am Chem Soc. 2007;129(46):14444–14451.
  • Ertekin E, Gencturk E, Kasim M, et al. A drug repurposing and protein–protein interaction network study of ribosomopathies using yeast as a model system. OMICS. 2020;24
  • Nag S, Qin JJ, Srivenugopal K, et al. The MDM2-p53 pathway revisited. J Biomed Res. 2013;27(4):254–271.
  • Vousden KH, Lane DP. p53 in health and disease. Nat Rev Mol Cell Biol. 2007;8(4):275–283.
  • Vousden KH, Prives C. Blinded by the light: the growing complexity of p53. Cell. 2009;137(3):413–431.
  • Levine AJ, Oren M. The first 30 years of p53: growing ever more complex. Nat Rev Cancer. 2009;9(10):749–758.
  • Toledo F, Wahl GM. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer. 2006;6(12):909–923.
  • Crighton D, Woiwode A, Zhang C, et al. p53 represses RNA polymerase III transcription by targeting TBP and inhibiting promoter occupancy by TFIIIB. EMBO J. 2003;22:2810–2820.
  • Juven T, Barak Y, Zauberman A, et al. Wild type p53 can mediate sequence-specific transactivation of an internal promoter within the mdm2 gene. Oncogene. 1993;8(12):3411–3416.
  • Wu X, Bayle JH, Olson D, et al. The p53-mdm-2 autoregulatory feedback loop. Genes Dev. 1993;7(7A):1126–1132.
  • Barak Y, Juven T, Haffner R, et al. mdm2 expression is induced by wild type p53 activity. EMBO J. 1993;12(2):461–468.
  • Oliner JD, Pietenpol JA, Thiagalingam S, et al. Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature. 1993;362(6423):857–860.
  • Haupt Y, Maya R, Kazaz A, et al. Mdm2 promotes the rapid degradation of p53. Nature. 1997;387(6630):296–299.
  • Kubbutat MH, Jones SN, Vousden KH. Regulation of p53 stability by Mdm2. Nature. 1997;387(6630):299–303.
  • Honda R, Tanaka H, Oncoprotein YH. MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett. 1997;420:25–27.
  • Michael D, Oren M. The p53-Mdm2 module and the ubiquitin system. Semin Cancer Biol. 2003;13:49–58.
  • Zhang Y, Xiong Y, Yarbrough WG. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell. 1998;92(6):725–734.
  • Weber JD, Taylor LJ, Roussel MF, et al. Nucleolar Arf sequesters Mdm2 and activates p53. Nat Cell Biol. 1999;1(1):20–26.
  • Zhang Y, Lu H. Signaling to p53: ribosomal proteins find their way. Cancer Cell. 2009;16(5):369–377.
  • Miliani de Marval PL, Zhang Y. The RP-Mdm2-p53 pathway and tumorigenesis. Oncotarget. 2011;2(3):234–238.
  • Lohrum MAE, Ludwig RL, Kubbutat MHG, et al. Regulation of HDM2 activity by the ribosomal protein L11. Cancer Cell. 2003;3:577–587.
  • Zhang Y, Wolf GW, Bhat K, et al. Ribosomal protein L11 negatively regulates oncoprotein MDM2 and mediates a p53-dependent ribosomal-stress checkpoint pathway. Mol Cell Biol. 2003;23:8902–8912.
  • Dai MS, Lu H. Inhibition of MDM2-mediated p53 ubiquitination and degradation by ribosomal protein L5. J Biol Chem. 2004;279:44475–44482.
  • Liu Y, Deisenroth C, Zhang Y. Zhang Y. RP-MDM2-p53 pathway: linking ribosomal biogenesis and tumor surveillance. Trends Cancer. 2016;2:191–204.
  • Deisenroth C, Zhang Y. Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53n pathway. Oncogene. 2010;29:4253–4260.
  • Penzo M, Montanaro L, Treré D, et al., The ribosome biogenesis-cancer connection. Cells. 8(1): 55. 2019.
  • Rubbi CP, Milner J. Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses. EMBO J. 2003;22:6068–6077.
  • Kurki S, Peltonen K, Latonen L, et al. Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2-mediated degradation. Cancer Cell. 2004;5:465–475.
  • Dhar SK, St Clair DK. Nucleophosmin blocks mitochondrial localization of p53 and apoptosis. J Biol Chem. 2009;284:16409–16418.
  • Sun XX, Dai MS, Lu H. 5-fluorouracil activation of p53 involves an MDM2- ribosomal protein interaction. J Biol Chem. 2007;282:8052–8059.
  • Sun XX, Dai MS, Lu H. Mycophenolic acid activation of p53 requires ribosomal proteins L5 and L11. J Biol Chem. 2008;283:12387–12392.
  • Donati G, Bertoni S, Brighenti E, et al. The balance between rRNA and ribosomal protein synthesis up- and downregulates the tumour suppressor p53 in mammalian cells. Oncogene. 2011;30(29):3274–3288.
  • Balch WE, Morimoto RI, Dillin A, et al. Manipulating proteostasis for disease intervention. Science. 2008;319:916–919.
  • Dai MS, Zeng SX, Jin Y, et al. Ribosomal protein L23 activates p53 by inhibiting MDM2 function in response to ribosomal perturbation but not to translation inhibition. Mol Cell Biol. 2004;24:7654–7668.
  • Espinoza JA, Zisi A, Kanellis DC, et al. The antimalarial drug amodiaquine stabilizes p53 through ribosome biogenesis stress, independently of its autophagy-inhibitory activity. Cell Death Differ. 2020;27:773–789.
  • Scala F, Brighenti E, Govoni M, et al. Direct relationship between the level of p53 stabilization induced by rRNA synthesis-inhibiting drugs and the cell ribosome biogenesis rate. Oncogene. 2016;35(8):977–989.
  • Carpenter RL, Gokmen-Polar Y. HSF1 as a cancer biomarker and therapeutic target. Curr Cancer Drug Targets. 2019;19:515–524.
  • Wu CT, Lin TY, Hsu HY, et al. Ling Zhi-8 mediates p53-dependent growth arrest of lung cancer cells proliferation via the ribosomal protein S7-MDM2-p53 pathway. Carcinogenesis. 2011;32(12):1890–1896.
  • Donati G, Montanaro L, Derenzini M. Ribosome biogenesis and control of cell proliferation: p53 is not alone. Cancer Res. 2012;72:1602–1607.
  • Lindstrom MS, Jin A, Deisenroth C, et al. Cancer-associated mutations in the MDM2 zinc finger domain disrupt ribosomal protein interaction and attenuate MDM2-induced p53 degradation. Mol Cell Biol. 2007;27(3):1056–1068.
  • Kondoh N, Shuda M, Tanaka K, et al. Enhanced expression of S8, L12, L23a, L27 and L30 ribosomal protein mRNAs in human hepatocellular carcinoma. Anticancer Res. 2001;21(4A):2429–2433.
  • Russo A, Russo G. Ribosomal proteins control or bypass p53 during nucleolar stress. Int J Mol Sci. 2017;18(1):140.
  • Derenzini M, Montanaro L, Trere D. Ribosome biogenesis and cancer. Acta Histochem. 2017;119:190–197.
  • Gomez-Roman N, Felton-Edkins ZA, Kenneth NS, et al. Activation by c-Myc of transcription by RNA polymerases I, II and III. Biochem Soc Symp. 2006;73:141–154.
  • van Riggelen J, Yetil A, Felsher DW. MYC as a regulator of ribosome biogenesis and protein synthesis. Nat Rev Cancer. 2010;10:301–309.
  • Yin Y, Hua H, Li M, et al. mTORC2 promotes type I insulin-like growth factor receptor and insulin receptor activation through the tyrosine kinase activity of mTOR. Cell Res. 2016;26:46–65.
  • Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017;168:960–976.
  • Stefanovsky VY, Pelletier G, Hannan R, et al. An immediate response of ribosomal transcription to growth factor stimulation in mammals is mediated by ERK phosphorylation of UBF. Mol Cell. 2001;8:1063–1073.
  • Stefanovsky V, Langlois F, Gagnon-Kugler T, et al. Growth factor signaling regulates elongation of RNA polymerase I transcription in mammals via UBF phosphorylation and r-chromatin remodeling. Mol Cell. 2006;21:629–639.
  • Grummt I. Wisely chosen paths–regulation of rRNA synthesis: delivered on 30 June 2010 at the 35th FEBS congress in Gothenburg, Sweden. FEBS J. 2010;277:4626–4639.
  • Gentilella A, Kozma SC, Thomas G. A liaison between mTOR signaling, ribosome biogenesis and cancer. Biochim Biophys Acta. 2015;1849:812–820.
  • Zinzalla V, Stracka D, Oppliger W, et al. Activation of mTORC2 by association with the ribosome. Cell. 2011;144:757–768.
  • Dienstmann R, Rodon J, Serra V, et al. Picking the point of inhibition: a comparative review of PI3K/AKT/mTOR pathway inhibitors. Mol Cancer Ther. 2014;13:1021–1031.
  • Abraham J. PI3K/AKT/mTOR pathway inhibitors: the ideal combination partners for breast cancer therapies? Expert Rev Anticancer Ther. 2015;15:51–68.
  • Janku F, Wheler JJ, Naing A, et al. PIK3CA mutation H1047R is associated with response to PI3K/AKT/mTOR signaling pathway inhibitors in early-phase clinical trials. Cancer Res. 2013;73(1):276–284.
  • Ribosomal Protein MO. S6 phosphorylation: four decades of research. Int Rev Cell Mol Biol. 2015;320:41–73.
  • Sun CK, Zhang F, Xiang T, et al. Phosphorylation of ribosomal protein S6 confers PARP inhibitor resistance in BRCA1-deficient cancers. Oncotarget. 2014;5:3375–3385.
  • Hsieh AC, Costa M, Zollo O, et al. Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E. Cancer Cell. 2009;17:249–261.
  • Vadivel Gnanasundram S, Translation Stress FR. Regulates ribosome synthesis and cell proliferation. Int J Mol Sci. 2018;19(12):3757.
  • Burris HA, Kurkjian CD, Hart L. 3rd, Kurkjian CD, hart L, et al. TAK- 228 (formerly MLN0128), an investigational dual TORC1/2 inhibitor plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies. Cancer Chemother Pharmacol. 2017;80:261–273.
  • Slotkin EK, Patwardhan PP, Vasudeva SD, et al. MLN0128, an ATP-competitive mTOR kinase inhibitor with potent in vitro and in vivo antitumor activity, as potential therapy for bone and soft-tissue sarcoma. Mol Cancer Ther. 2015;14:395–406.
  • Gökmen-Polar Y, Liu Y, Toroni RA, et al. Investigational drug MLN0128, a novel TORC1/2 inhibitor, demonstrates potent oral antitumor activity in human breast cancer xenograft models. Breast Cancer Res Treat. 2012;136:673–682.
  • Rashid MM, Lee H, Jung BH. Metabolite identification and pharmacokinetic profiling of PP242, an ATP-competitive inhibitor of mTOR using ultra high-performance liquid chromatography and mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2018;1072:244–251.
  • Feldman ME, Apsel B, Uotila A, et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 2009;7:e38.
  • Guichard SM, Curwen J, Bihani T, et al. AZD2014, an inhibitor of mTORC1 and mTORC2, is highly effective in ER+ breast cancer when administered using intermittent or continuous schedules. Mol Cancer Ther. 2015;14:2508–2518.
  • Jordan NJ, Dutkowski CM, Barrow D, et al. Impact of dual mTORC1/2 mTOR kinase inhibitor AZD8055 on acquired endocrine resistance in breast cancer in vitro. Breast Cancer Res. 2014;16:R12.
  • Chiarini F, Evangelisti C, McCubrey JA, et al. Current treatment strategies for inhibiting mTOR in cancer. Trends Pharmacol Sci. 2015;36:124–135.
  • Zaidi AH, Kosovec JE, Matsui D, et al. PI3K/mTOR dual inhibitor, LY3023414, demonstrates potent antitumor efficacy against esophageal adenocarcinoma in a rat model. Ann Surg. 2017;266:91–98.
  • Yu P, Laird AD, Du X, et al. Characterization of the activity of the PI3K/mTOR inhibitor XL765 (SAR245409) in tumor models with diverse genetic alterations affecting the PI3K pathway. Mol Cancer Ther. 2014;13:1078–1091.
  • Hua H, Kong Q, Zhang H, et al. Targeting mTOR for cancer therapy. J Hematol Oncol. 2019;12(1):71.
  • Beaufils F, Cmiljanovic N, Cmiljanovic V, et al. 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2- amine (PQR309), a potent, brain-penetrant, orally bioavailable, pan-class I PI3K/mTOR inhibitor as clinical candidate in oncology. J Med Chem. 2017;60:7524–7538.
  • Brandt C, Hillmann P, Noack A, et al. The novel, catalytic mTORC1/2 inhibitor PQR620 and the PI3K/mTORC1/2 inhibitor PQR530 effectively cross the blood-brain barrier and increase seizure threshold in a mouse model of chronic epilepsy. Neuropharmacology. 2018;140:107–120.
  • Venkatesan AM, Dehnhardt CM, Delos Santos E, et al. Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5’-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor. J Med Chem. 2010;53:2636–2645.
  • Knight SD, Adams ND, Burgess JL, et al. Discovery of GSK2126458, a highly potent inhibitor of PI3K and the mammalian target of rapamycin. ACS Med Chem Lett. 2010;1:39–43.
  • Hua H, Zhang H, Kong Q, et al. Complex roles of the old drug aspirin in cancer chemoprevention and therapy. Med Res Rev. 2019;39:114–145.
  • Boyle KA, Van Wickle J, Hill RB, et al. Mitochondria-targeted drugs stimulate mitophagy and abrogate colon cancer cell proliferation. J Biol Chem. 2018;293:14891–14904.
  • Ling S, Xie H, Yang F, et al. Metformin potentiates the effect of arsenic trioxide suppressing intrahepatic cholangiocarcinoma: roles of p38 MAPK, ERK3, and mTORC1. J Hematol Oncol. 2017;10:59.
  • Fan QW, Cheng CK, Nicolaides TP, et al. A dual phosphoinositide-3-kinase a/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma. Cancer Res. 2007;67:7960–7965.
  • Rehan M, Saleem M. Anticancer compound XL765 as PI3K/mTOR dual inhibitor: a structural insight into the inhibitory mechanism using computational approaches. PLoS One. 2019;14(6):e0219180.
  • Bhatt AP, Bhende PM, Sin SH, et al. Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas. Blood. 2010;115(22):4455–4463.
  • Chen X, Zhao M, Hao M, et al. Dual inhibition of PI3K and mTOR mitigates compensatory AKT activation and improves tamoxifen response in breast cancer. Mol Cancer Res. 2013;11(10):1269–1278.
  • Hu X, Xia M, Wang J, et al. Dual PI3K/mTOR inhibitor PKI-402 suppresses the growth of ovarian cancer cells by degradation of Mcl-1 through autophagy. Biomed Pharmacother. 2020;129:110397.
  • Bhat M, Robichaud N, Hulea L, et al. Targeting the translation machinery in cancer. Nat Rev Drug Discov. 2015;14:261–278.
  • Harper JW, Bennett EJ. Proteome complexity and the forces that drive proteome imbalance. Nature. 2016;537:328–338.
  • Tubbs A, Endogenous NA. DNA damage as a source of genomic instability in cancer. Cell. 2017;168:644–656.
  • Skrott Z, Mistrik M, Andersen KK, et al. Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Nature. 2017;552:194–199.
  • Santagata S, Mendillo ML, Tang YC, et al. Tight coordination of protein translation and HSF1 activation supports the anabolic malignant state. Science. 2013;341:1238303.
  • Valvezan AJ, Turner M, Belaid A, et al. mTORC1 couples nucleotide synthesis to nucleotide demand resulting in a targetable metabolic vulnerability. Cancer Cell. 2017;32(5):624–638.
  • Xu Y, Ruggero D. The role of translation control in tumorigenesis and its therapeutic implications. Annu Rev Cancer Biol. 2019;4:437–457.
  • Pelletier J, Thomas G, Volarevic S. Ribosome biogenesis in cancer: new players and therapeutic avenues. Nat Rev Cancer. 2018;18:51–63.
  • Draptchinskaia N, Gustavsson P, Andersson B, et al. The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. Nat Genet. 1999;21(2):169–175.
  • Gazda HT, Grabowska A, Merida-Long LB, et al. Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia. Am J Hum Genet. 2006;79(6):1110–1118.
  • Cmejla R, Cmejlova J, Handrkova H, et al. Ribosomal protein S17 gene (RPS17) is mutated in Diamond-Blackfan anemia. Hum Mutat. 2007;28(12):1178–1182.
  • Song MJ, Yoo EH, Lee KO, et al. A novel initiation codon mutation in the ribosomal protein S17 gene (RPS17) in a patient with Diamond-Blackfan anemia. Pediatr Blood Cancer. 2010;54(4):629–631.
  • Cmejla R, Cmejlova J, Handrkova H, et al. Identification of mutations in the ribosomal protein L5 (RPL5) and ribosomal protein L11 (RPL11) genes in Czech patients with Diamond-Blackfan anemia. Hum Mutat. 2009;30(3):321–327.
  • Gazda HT, Sheen MR, Vlachos A, et al. Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond Blackfan anemia patients. Am J Hum Genet. 2008;83(6):769–780.
  • Gazda HT, Preti M, Sheen MR, et al. Frameshift mutation in p53 regulator RPL26 is associated with multiple physical abnormalities and a specific pre-ribosomal RNA processing defect in Diamond-Blackfan anemia. Hum Mutat. 2012;33(7):1037–1044.
  • Farrar JE, Nater M, Caywood E, et al. Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond-Blackfan anemia. Blood. 2008;112(5):1582–1592.
  • Doherty L, Sheen MR, Vlachos A, et al. Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia. Am J Hum Genet. 2010;86(2):222–228.
  • Landowski M, O’Donohue MF, Buros C, et al. Novel deletion of RPL15 identified by array-comparative genomic hybridization in Diamond-Blackfan anemia. Hum Genet. 2013;132(11):1265–1274.
  • Barlow JL, Drynan LF, Trim NL, et al. New insights into 5q- syndrome as a ribosomopathy. Cell Cycle. 2010;9(21):4286–4293.
  • Jones NC, Lynn ML, Gaudenz K, et al. Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function. Nat Med. 2008;14(2):125–133.
  • Sakai D, Trainor PA. Treacher Collins syndrome: unmasking the role of Tcof1/treacle. Int J Biochem Cell Biol. 2009;41(6):1229–1232.
  • Ganapathi KA, Shimamura A. Ribosomal dysfunction and inherited marrow failure. Br J Haematol. 2008;141(3):376–387.
  • Burroughs L, Woolfrey A, Shimamura A. Shwachman-Diamond syndrome: a review of the clinical presentation, molecular pathogenesis, diagnosis, and treatment. Hematol Oncol Clin North Am. 2009;23(2):233–248.
  • Boocock GR, Morrison JA, Popovic M, et al. Mutations in SBDS are associated with Shwachman-Diamond syndrome. Nat Genet. 2003;33(1):97–101.
  • Weis F, Giudice E, Churcher M, et al. Mechanism of eIF6 release from the nascent 60S ribosomal subunit. Nat Struct Mol Biol. 2015;22(11):914–919.
  • Finch AJ, Hilcenko C, Basse N, et al. Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome. Genes Dev. 2011;25(9):917–929.
  • Morini J, Babini G, Mariotti L, et al. Radiosensitivity in lymphoblastoid cell lines derived from Shwachman–Diamond syndrome patients. Radiat Prot Dosimetry. 2015;166(1–4):95–100.
  • Toiviainen-Salo S, Mäyränpää MK, Durie PR, et al. Shwachman-Diamond syndrome is associated with low-turnover osteoporosis. Bone. 2007;41(6):965–972.
  • Qiu XB, Shao YM, Miao S, et al. The diversity of the DnaJ/ Hsp40 family, the crucial partners for Hsp70 chaperones. Cell Mol Life Sci. 2006;63(22):2560–2570.
  • Quelle DE, Zindy F, Ashmun RA, et al. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell. 1995;83:993–1000.
  • Tikoo S, Sengupta S. Time to bloom. Genome Integr. 2010;1:14.
  • Shiratori M, Suzuki T, Itoh C, et al. WRN helicase accelerates the transcription of ribosomal RNA as a component of an RNA polymerase I-associated complex. Oncogene. 2002;21:2447–2454.
  • Rossi ML, Ghosh AK, Bohr VA. Roles of Werner syndrome protein in protection of genome integrity. DNA Repair (Amst). 2010;9:331–344.
  • Natale V. A comprehensive description of the severity groups in Cockayne syndrome. Am J Med Genet A. 2011;155A:1081–1095.
  • Laugel V, Dalloz C, Durand M, et al. Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in Cockayne syndrome. Hum Mutat. 2010;31:113–126.
  • Bradsher J, Auriol J, Proietti de Santis L, et al. CSB is a component of RNA pol I transcription. Mol Cell. 2002;10:819–829.
  • Laumonnier F, Holbert S, Ronce N, et al. Mutations in PHF8 are associated with X linked mental retardation and cleft lip/cleft palate. J Med Genet. 2005;42:780–786.
  • Lisik MZ, Sieron AL. X-linked mental retardation. Med Sci Monit. 2008;14:RA221–RA229.
  • Dawson MA, Bannister AJ. Demethylases go mental. Mol Cell. 2010;38:155–157.
  • Kleine-Kohlbrecher D, Christensen J, Vandamme J, et al. A functional link between the histone demethylase PHF8 and the transcription factor ZNF711 in X-linked mental retardation. Mol Cell. 2010;38:165–178.
  • Loenarz C, Ge W, Coleman ML, et al. PHF8, a gene associated with cleft lip/palate and mental retardation, encodes for an Nepsilondimethyl lysine demethylase. Hum Mol Genet. 2010;19:217–222.
  • Bose T, Lee KK, Lu S, et al. Cohesin proteins promote ribosomal RNA production and protein translation in yeast and human cells. PLoS Genet. 2012;8e:1002749.
  • Feng W, Yonezawa M, Ye J, et al. PHF8 activates transcription of rRNA genes through H3K4me3 binding and H3K9me1/2 demethylation. Nat Struct Mol Biol. 2010;17:445–450.
  • Ide S, Miyazaki T, Maki H, et al. Abundance of ribosomal RNA gene copies maintains genome integrity. Science. 2010;327:693–696.
  • Velkova A, Carvalho MA, Johnson JO, et al. Identification of Filamin A as a BRCA1-interacting protein required for efficient DNA repair. Cell Cycle. 2010;9:1421–1433.
  • Najib S, Saint-Laurent N, Esteve JP, et al. A switch of G protein-coupled receptor binding preference from phosphoinositide 3-kinase (PI3K)-p85 to filamin A negatively controls the PI3K pathway. Mol Cell Biol. 2012;32:1004–1016.
  • Zhou AX, Hartwig JH, Akyurek LM. Filamins in cell signaling, transcription and organ development. Trends Cell Biol. 2010;20:113–123.
  • Yuan Y, Shen Z. Interaction with BRCA2 suggests a role for filamin-1 (hsFLNa) in DNA damage response. J Biol Chem. 2001;276:48318–48324.
  • Yue J, Lu H, Liu J, et al. Filamin-A as a marker and target for DNA damage based cancer therapy. DNA Repair (Amst). 2012;11:192–200.
  • Deng W, Lopez-Camacho C, Tang JY, et al. Cytoskeletal protein filamin A is a nucleolar protein that suppresses ribosomal RNA gene transcription. Proc Natl Acad Sci. U S A. 2012; 109: 1524–1529.
  • Quin JE, Devlin JR, Cameron D, et al. Targeting the nucleolus for cancer intervention. Biochim Biophys Acta. 2014;1842(6):802–816.
  • Boulon S, Westman BJ, Hutten S, et al. The nucleolus under stress. Mol Cell. 2010;40:216–227.
  • Siebert A, Prejs M, Cholewinski G, et al. New analogues of mycophenolic acid. Mini Rev Med Chem. 2017;17(9):734–745.
  • Yi SA, Nam KH, Kim S, et al. Vulpinic acid controls stem cell fate toward osteogenesis and adipogenesis. Genes (Basel). 2019;11(1):18.
  • Xu H, Di Antonio M, McKinney S, et al. CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours. Nat Commun. 2017;8:14432.
  • Hernandez-Verdun D, Roussel P, Thiry M, et al. The nucleolus: structure/function relationship in RNA metabolism. Wiley Interdiscip Rev RNA. 2010;1:415–431.
  • Peltonen K, Colis L, Liu H, et al. Identification of novel p53 pathway activating small-molecule compounds reveals unexpected similarities with known therapeutic agents. PLoS One. 2010;5:e12996.
  • Soundararajan S, Chen W, Spicer EK, et al. The nucleolin targeting aptamer AS1411 destabilizes Bcl-2 messenger RNA in human breast cancer cells. Cancer Res. 2008;68:2358–2365.
  • Di Matteo A, Franceschini M, Chiarella S, et al. Molecules that target nucleophosmin for cancer treatment: an update. Oncotarget. 2016;7:44821–44840.
  • Rathner A, Rathner P, Friedrich A, et al. Drug development for target ribosomal protein rpL35/uL29 for repair of LAMB3R635X in rare skin disease epidermolysis bullosa. Skin Pharmacol Physiol. 2021;6:1–16.
  • Alter BP, Giri N, Savage SA, et al. Cancer in dyskeratosis congenita. Blood. 2009;113(26):6549–6557. https://medlineplus.gov/genetics/condition/dyskeratosis-congenita
  • Baran I, Nalcaci R, Kocak M. Dyskeratosis congenita: clinical report and review of the literature. Int J Dent Hyg. 2010;8(1):68–74.
  • Keller RB, Gagne KE, Usmani GN, et al. CTC1 Mutations in a patient with dyskeratosis congenita. Pediatr Blood Cancer. 2012;59(2):311–314.
  • Le Guen T, Jullien L, Touzot F, et al. Human RTEL1 deficiency causes hoyeraal-hreidarsson syndrome with short telomeres and genome instability. Hum Mol Genet. 2013;22(16):3239–3249.
  • Ganapathi KA, Shimamura A. Ribosomal dysfunction and inherited marrow failure. Br J Haematol. 2008;141(3):376–387.
  • Martin AN, Li Y. RNase MRP RNA and human genetic diseases. Cell Res. 2007;17(3):219–226.
  • Matesic D, Hagan JB. Cartilage-hair hypoplasia. Mayo Clin Proc. 2007;82(6):655.
  • Mattijssen S, Welting TJ, Pruijn GJ. RNase MRP and disease. Wiley Interdiscip Rev RNA. 2010;1(1):102–116. https://medlineplus.gov/genetics/condition/cartilage-hair-hypoplasia
  • Lafontaine DL. Noncoding RNAs in eukaryotic ribosome biogenesis and function. Nat Struct Mol Biol. 2015;22:11–19.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.