Download PDF
CC BY-NC-ND 4.0 · Journal of Health and Allied Sciences NU 2015; 05(03): 087-092
DOI: 10.1055/s-0040-1703918
Review Article

Faulty ribosomes and human diseases: mistakes in “assembly line” going unnoticed ?

Anirban Chakraborty
1   Associate Professor, Division of Molecular Genetics and Cancer, Nitte University Centre for Science Education and Research, Nitte University, Mangalore, Karnataka, India
,
Indrani Karunasagar
2   Professor &Director (R&D), Dean, Faculty of Biological Sciences, Nitte University Centre for Science Education and Research, Nitte University, Mangalore, Karnataka, India
› Author Affiliations
› Further Information
Also available at
  PDF Download Permissions and Reprints

Abstract

Ribosomes are molecular machineries that decode the information within mRNAs and generate all the proteins required for cellular activities. Ribosomes are essential to every living organism. The synthesis of ribosome is an intricate process, which is carried out in multiple steps throughout the cell in a highly coordinated fashion. For many years, the general perception was that any defects in the “ribosome assembly line” would have fatal consequences on cell. However, it has now become clear that production of defective ribosomes does not lead to lethality in human embryos. Rather, it manifests as specific disease conditions called ribosomopathies, which are rare genetic disorders affecting the bone marrow. This group of diseases has received considerable attention in recent years because of the mystery associated with them i.e. the tissue-specific nature of the clinical phenotypes despite the fact that the genes mutated in patients code for proteins that are absolutely essential and are housekeeping in nature. Despite considerable progress in understanding these diseases, it still remains unclear why defects in the production of a macromolecule as indispensable and as ubiquitous as the ribosome go unnoticed and why the effects are not universal but rather are restricted to specific cell types. This review is aimed at introducing the readers to important ribosomopathies with a brief description about the clinical symptoms, molecular genetics, and the treatments strategies.

Keywords

Ribosome - Ribosomopathies - Ribosomal Proteins - Inherited Bone Marrow Failure Syndromes - Anemia


Publication History

Article published online:
22 April 2020

© .

Thieme Medical and Scientific Publishers Private Ltd.
A-12, Second Floor, Sector -2, NOIDA -201301, India

 

  • References

  • 1 Wool IG. The structure and function of eukaryotic ribosomes. Ann Rev Biochem1979; 48:719 – 754.
  • 2 Chakraborty A, Kenmochi N. Ribosomes and ribosomal proteins: More than just 'housekeeping' Els In: eLS. Chichester: John Wiley & Sons, Ltd; 2012.
  • 3 http://rdp.cme.msu.edu/index.jsp (accessed August 11, 2015).
  • 4 http://ribosome.med.miyazaki-u.ac.jp (accessed August 11, 2015).
  • 5 Warner JR. The economics of ribosome biosynthesis in yeast. Trends Biochem Sci1999; 24:437–440.
  • 6 Chakraborty A, Uechi T, Kenmochi N. Guarding the translation apparatus: defective ribosome biogenesis and the p53 signaling pathway. Wiley Interdisciplinary Reviews: RNA 2011; 2:507–522.
  • 7 Thomson E, Sebastien F-C, Hurt Ed. Eukaryotic ribosome biogenesis at a glance. J Cell Science 2013; 126:4815-4821.
  • 8 https://cmns.umd.edu/news-events/news/1999 (accessed August 11, 2015)
  • 9 Lam YW, Trinkle-Mulcahy L, Lamond AI. The nucleolus. J Cell Science 2005; 118:1335–1337.
  • 10 Emmott E, Hiscox JA. Nucleolar targeting: the hub of the matter. EMBO Reports 2009; 10: 231–238.
  • 11 Narla A, Ebert BL. Ribosomopathies: human disorders of ribosome dysfunction. Blood2010; 115:3196 – 3205.
  • 12 Freed EF, Bleichert F, Dutca LM, Baserga SJ. When ribosomes gobad: diseases of ribosome biogenesis. Mol Biosys 2010; 6:481–493.
  • 13 Vlachos A, Ball S, Dahl N, Alter BP, Sheth S, Ramenghi U, et al. Diagnosing and treating Diamond Blackfan anemia: results of an international clinical consensus conference. Br J Haematol 2008; 142:859-876.
  • 14 Vlachos A, Muir E. How I treat Diamond Blackfan anemia. Blood 2010; 116: 3715-3723.
  • 15 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: 233-248.
  • 16 Johnson AW, Ellis SR. Of Blood, bones, and ribosomes: is Swachman- Diamond syndrome a ribosomopathy? Genes and Development 2011; 25: 898-900.
  • 17 Zhang S, Shi M, Hui CC, Rommens JM. Loss of the mouse ortholog of the shwachman-diamond syndrome gene (Sbds) results in early embryonic lethality. Mol Cell Biol 2006; 26: 6656– 6663.
  • 18 Moore JB IV, Farrar JE, Arceci RJ, Liu JM, Ellis SR. Distinct ribosome maturation defects in yeast models of Diamond- Blackfan anemia and Shwachman-Diamond syndrome. Haematologica 2010; 95: 57–64.
  • 19 Austin KM, Leary RJ, Shimamura A. The Shwachman- Diamond SBDS protein localizes to the nucleolus. Blood 2005; 106: 1253–1258.
  • 20 Finch AJ, Hilcenko C, Basse N, Drynan LF, Goyenechea B, Menne TF, et al. Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome. Genes and Development 2011; 25: 917-29.
  • 21 Dokal I. Dyskeratosis Congenita. Hematology The American Society of Hematology Education Program Book 1: 2011; 480–486.
  • 22 Heiss NS, Knight SW, Vulliamy TJ, Klauck SM, Wiemann S, Mason PJ, et al. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat Genet1998; 19:32–38.
  • 23 Yoon A, Peng G, Brandenburg Y, Zollo O, Xu W, Rego E, et al. Impaired control of IRES- mediated translation in X-linked dyskeratosis congenita. Science2006; 312:902–906.
  • 24 Calado RT, Young NS. Telomere maintenance and human bone marrow failure. Blood 2008; 111:4446 – 4455.
  • 25 Nelson ND, Bertuch AA. Dyskeratosis congenital as a disorder of telomere maintenance. Mut Res 2012; 730: 43-51.
  • 26 Montanaro L, Calieni M, Bertoni S, Rocchi L, Sansone P, Storci G, et al. Novel dyskerin-mediated mechanism of p53 inactivation through defective mRNA translation. Cancer Res2010; 70:4767 – 4777.
  • 27 Suneet A, Loh Y-H, McLoughlin EM, Huang J, Park I-H, Miller JD, et al. Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients. Nature 2010; 464: 292-296.
  • 28 Van den Berghe H, Cassiman J, David G, Fryns JP, Michaux JL, Sokal G. Distinct hematological disorder with deletion of long arm of no. 5 chromosome. Nature1974; 251:437–438.
  • 29 Boultwood J, Fidler C, Strickson AJ, Watkins F, Gama S, Kearney L, et al. Narrowing and genomic annotation of the commonly deleted region of the 5q syndrome. Blood2002; 99:4638–4641.
  • 30 Ebert BL, Pretz J, Bosco J, Chang CY, Tamayo P, Galili N, et al. - Identification of RPS14 as a 5q syndrome gene by RNA interference screen. Nature2008; 451:335 – 339.
  • 31 Starczynowski DT, Kuchenbauer F, Argiropoulus B, Sung S, Morin R, Muranyi A, et al. Identification of miR-145 and miR-146a as mediators - of the 5q syndrome phenotype. Nat Med2010; 16:49–58.
  • 32 Dixon MJ. Treacher Collins syndrome. Hum Mol Genet 1996; 5:1391- 1396.
  • 33 Valdez BC, Henning D, So RB, Dixon J, Dixon MJ. The Treacher Collins syndrome (TCOF1) gene product is involved in ribosomal rDNA gene transcription by interacting with upstream binding factor. Proc Natl Acad Sci USA2004; 101:10709–10714.
  • 34 Gonzales B, Henning D, So RB, Dixon J, Dixon MJ, Valdez BC. The Treacher Collins syndrome (TCOF1) gene product is involved in prerRNA methylation. Hum Mol Genet2005; 14:2035–2043.
  • 35 Posnick JC, Ruiz RL. Treacher Collins syndrome: current evaluation, treatment, and future directions. Cleft Palate CraniofacialJ2000; 37:434.
  • 36 Mahlaoui N, Minard-Colin V, Picard C, Bolze A, Ku C-L, Tournilhac O, et al. Isolated congenital asplenia: a French nationwide retrospective survey of 20 cases. J. Pediat 2011;158: 142-148.
  • 37 Bolze A, Mahlaoui N, Byun M, Turner B, Trede N, Ellis SR, et al. Ribosomal protein SA haploinsufficiency in humans with isolated congenital asplenia. Science 2013; 340: 976-978.
  • 38 Chagnon P, Michaud J, Mitchell G, Mercier J, Marion J, Drouin E, et al. A missense mutation (R565W) in cirhin (FLJ14728) in North American Indian childhood cirrhosis. Am J Hum Genet 2002; 71: 1443–1449.
  • 39 WadJm Cell Biol 2014; 92: 191-199.
  • 40 Be tard C, Rasquin-Weber A, Brewer C, Drouin E, Clark S, Verner A, et al. Localization of a recessive gene for North American Indian childhood cirrhosis to chromosome region 16q22-and identification of a shared haplotype. Am J Hum Genet 2000; 67: 222–228.
  • 41 McCann KL, Baserga SJ. Mysterious Ribosomopathies. Science 2013; 341: 849-850.
  • 42 Xue S, Barna M. Specialized ribosomes: a new frontier in gene regulation and organismal biology. Nature Reviews: Mol Cell Biol 2012; 13: 355-369.
  • 43 Kondrashov N, Pusic A, Stumpf CR, Shimizu K, Hsieh AC, Xue S, et al. Ribosome-mediated specificity in Hox mRNA translation and vertebrate tissue patterning. Cell 2011; 145, 383-397.