Implications of RNA‐binding Proteins for Human Diseases

Kiven E Lukong, University of Saskatchewan, Saskatoon, Canada
Rachid El Fatimy, Université Laval, Beauport (Québec), Canada

Published online: May 2012

DOI: 10.1002/9780470015902.a0023866

RNA‐binding proteins play pivotal roles in ribonucleic acid (RNA) metabolism. The identification of mRNA targets of RNA‐binding proteins has also contributed to the delineation function of these proteins. The different tissue specificity and subcellular localisation of the RNA‐binding proteins show that these proteins can regulate specific aspects of mRNA processing and function in cells, from splicing and transport to translation and stability. Mutations, deletions and/or autoimmune reactions affecting RNA‐binding proteins lead to alterations in cellular processes, normal development and various disorders. The vast majority of these diseases are neurological or neuromuscular disorders and includes myotonic dystrophy, spinal muscular atrophy, oculopharyngeal muscular dystrophy, amyotrophic lateral sclerosis, fragile X syndrome, fragile X associated tremor/ataxia syndrome and paraneoplastic opsoclonus‐myoclonus ataxia. Altered expression of RNA‐binding proteins is also a common feature in various cancers. Understanding the molecular mechanisms of RNA‐binding proteins aberrations in disease could lead to better‐targeted therapies.

Key Concepts:

  • RNA‐binding proteins are key components in RNA metabolism.
  • RNA‐binding proteins contain modular amino acid sequences that mediate RNA binding.
  • The two largest RBP families contain the RNA recognition motif (RRM) and the K homology (KH) domains.
  • Deleterious RNA‐dominant loss‐of‐function or gain‐of‐function mechanisms are associated with defects in RBPs.
  • Several neurological and neuro‐muscular diseases are linked to defects in RBPs.
  • FXS is caused by CGG repeat in the 5′ untranslated region of the FMR1 gene.
  • Antibodies against RBPs Hu and Nova are implicated in the pathogenesis of paraneoplastic neurologic syndromes.
  • DM1 is associated with the accumulation of RNA aggregates and misregulation of the RBPs, MBNL1 and CUGBP1.
  • Translocations of genes encoding RBPs and aberrant expression RBPs have been associated with various cancers.

Keywords: RNA binding proteins; complex human diseases; RNA metabolism; neurological disorders; cancer; RNA; neuromuscular diseases

Figure 1. Functional domains of some RBPs implicated in human diseases. Functional domains of some RNA‐binding proteins implicated in human diseases, showing variability in the RNA‐binding domains and size. These domains include the RNA‐recognition motif (RRM; by far the most common RNA‐binding protein module) and the K‐homology (KH) domain (which can bind both single‐stranded RNA and DNA). Less common RNA‐binding functional modules like the tudor domain found in SMN which bind RNA and methylated histones; zinc finger motifs CCCH (Cys3His or C3H motifs) or CCCH (CysCysHisCys) found in MBNL1, TTP and Lin‐28; CSD (cold‐shock domain) found in Lin‐28. Indicated key residues include R/S, Arg/Ser; P, proline; Y, tyrosine; G, glycine; A, alanine; K, lysine; and Q, glutamine. The RBPs shown include ASF/SF2, alternative splicing factor/splicing factor 2; CUGBP, CUG‐binding protein; FMRP, fragile X mental retardation protein; FUS/TLS, fused in sarcoma/translocated in liposarcoma; KSRP, KH type splicing regulatory protein; MBNL1, RNA‐binding proteins muscleblind‐like 1; Msi1, Musashi‐1; Nova 1 and 2, Neuro‐oncological ventral antigen 1 and 2; PABP, poly(A)‐binding protein 1; Sam68, src‐associated in mitosis, 68 kDa; SMN, survival motor neuron protein; TDP‐43, TAR (trans‐activation response) DNA and RNA‐binding protein 43; and TTP, tristetraprolin.
close
 References
    Akamatsu W, Fujihara H, Mitsuhashi T et al. (2005) The RNA‐binding protein HuD regulates neuronal cell identity and maturation. Proceedings of the National Academy of Sciences of the USA 102: 4625–4630.
    Apponi LH, Corbett AH and Pavlath GK (2011) RNA‐binding proteins and gene regulation in myogenesis. Trends in Pharmacological Sciences 32: 652–658.
    Auweter SD, Oberstrass FC and Allain FH (2006) Sequence‐specific binding of single‐stranded RNA: is there a code for recognition? Nucleic Acids Research 34: 4943–4959.
    Blumen SC, Brais B, Korczyn AD et al. (1999) Homozygotes for oculopharyngeal muscular dystrophy have a severe form of the disease. Annals of Neurology 46: 115–118.
    Brais B (2009) Oculopharyngeal muscular dystrophy: a polyalanine myopathy. Current Neurology and Neuroscience Reports 9: 76–82.
    Cartegni L and Krainer AR (2002) Disruption of an SF2/ASF‐dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1. Nature Genetics 30: 377–384.
    Castillero‐Trejo Y, Eliazer S, Xiang L, Richardson JA and Ilaria RL Jr (2005) Expression of the EWS/FLI‐1 oncogene in murine primary bone‐derived cells Results in EWS/FLI‐1‐dependent, ewing sarcoma‐like tumors. Cancer Research 65: 8698–8705.
    Comery TA, Harris JB, Willems PJ et al. (1997) Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits. Proceedings of the National Academy of Sciences of the USA 94: 5401–5404.
    Dion P, Shanmugam V, Gaspar C et al. (2005) Transgenic expression of an expanded (GCG)13 repeat PABPN1 leads to weakness and coordination defects in mice. Neurobiology Disorders 18: 528–536.
    Dormann D, Rodde R, Edbauer D et al. (2010) ALS‐associated fused in sarcoma (FUS) mutations disrupt Transportin‐mediated nuclear import. EMBO Journal 29: 2841–2857.
    Dreyfuss G, Kim VN and Kataoka N (2002) Messenger‐RNA‐binding proteins and the messages they carry. Nature Reviews Molecular Cell Biology 3: 195–205.
    book Farrar MA and Kiernan Matthew C (2011) Spinal Muscular Atrophy. Chichester: eLS John Wiley & Sons Ltd.
    Feiguin F, Godena VK, Romano G et al. (2009) Depletion of TDP‐43 affects Drosophila motoneurons terminal synapsis and locomotive behavior. FEBS Lett 583: 1586–1592.
    Greenway MJ, Andersen PM, Russ C et al. (2006) ANG mutations segregate with familial and ‘sporadic’ amyotrophic lateral sclerosis. Nat Genet 38: 411–413.
    Hammond SM, Gogliotti RG, Rao V et al. (2010) Mouse survival motor neuron alleles that mimic SMN2 splicing and are inducible rescue embryonic lethality early in development but not late. Plos One 5: e15887.
    Hsieh‐Li HM, Chang JG, Jong YJ et al. (2000) A mouse model for spinal muscular atrophy. Nature Genetics 24: 66–70.
    Jiang H, Mankodi A, Swanson MS, Moxley RT and Thornton CA (2004) Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons. Human Molecular Genetics 13: 3079–3088.
    Kanadia RN, Shin J, Yuan Y et al. (2006) Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy. Proceedings of the National Academy of Sciences of the USA 103: 11748–11753.
    Karni R, de Stanchina E, Lowe SW et al. (2007) The gene encoding the splicing factor SF2/ASF is a proto‐oncogene. Nature Structural & Molecular Biology 14: 185–193.
    Kawahara H, Imai T, Imataka H et al. (2008) Neural RNA‐binding protein Musashi1 inhibits translation initiation by competing with eIF4G for PABP. Journal of Cell Biology 181: 639–653.
    Kazarian M, Calbo J, Proost N et al. (2009) Immune response in lung cancer mouse model mimics human anti‐Hu reactivity. Journal of Neuroimmunology 217: 38–45.
    Klein AF, Gasnier E and Furling D (2011) Gain of RNA function in pathological cases: Focus on myotonic dystrophy. Biochimie 93: 2006–2012.
    Koukoui SD and Chaudhuri A (2007) Neuroanatomical, molecular genetic, and behavioral correlates of fragile X syndrome. Brain Research Reviews 53: 27–38.
    Kuyumcu‐Martinez NM, Wang GS and Cooper TA (2007) Increased steady‐state levels of CUGBP1 in myotonic dystrophy 1 are due to PKC‐mediated hyperphosphorylation. Molecular Cell 28: 68–78.
    Lagier‐Tourenne C and Cleveland DW (2009) Rethinking ALS: the FUS about TDP‐43. Cell 136: 1001–1004.
    other Lee M‐H and Schedl T (2006) RNA‐binding proteins, WormBook, ed. The C. elegans Research Community, WormBook, April 18, 2006. doi/10.1895/wormbook.1.79.1, http://www.wormbook.org.
    Li ZZ, Kondo T, Murata T et al. (2002) Expression of Hqk encoding a KH RNA binding protein is altered in human glioma. Japanese Journal of Cancer Research 93: 167–177.
    Lukong KE, Chang KW, Khandjian EW and Richard S (2008) RNA‐binding proteins in human genetic disease. Trends in Genetics 24: 416–425.
    Lukong KE, Larocque D, Tyner AL and Richard S (2005) Tyrosine phosphorylation of sam68 by breast tumor kinase regulates intranuclear localization and cell cycle progression. Journal of Biological Chemistry 280: 38639–38647.
    Lunde BM, Moore C and Varani G (2007) RNA‐binding proteins: modular design for efficient function. Nature Reviews Molecular Cell Biology 8: 479–490.
    Mankodi A, Wheeler TM, Shetty R et al. (2011) Progressive myopathy in an inducible mouse model of oculopharyngeal muscular dystrophy. Neurobiology of Disease 45: 539–546.
    Monani UR, Sendtner M, Coovert DD et al. (2000) The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(‐/‐) mice and results in a mouse with spinal muscular atrophy. Human Molecular Genetics 9: 333–339.
    Muddashetty RS, Nalavadi VC, Gross C et al. (2011) Reversible inhibition of PSD‐95 mRNA translation by miR‐125a, FMRP phosphorylation, and mGluR signaling. Molecular Cell 42: 673–688.
    Musunuru K (2003) Cell‐specific RNA‐binding proteins in human disease. Trends in Cardiovascular Medicine 13: 188–195.
    Okano H, Kawahara H, Toriya M et al. (2005) Function of RNA‐binding protein Musashi‐1 in stem cells. Experimental Cell Research 306: 349–356.
    Orr HT and Zoghbi HY (2007) Trinucleotide repeat disorders. Annual Review of Neuroscience 30: 575–621.
    Penagarikano O, Mulle JG and Warren ST (2007) The Pathophysiology of Fragile X Syndrome. Annual Review of Genomics and Human Genetics. 8: 109–129.
    Rees JH (2004) Paraneoplastic syndromes: when to suspect, how to confirm, and how to manage. Journal of Neurology, Neurosurgery & Psychiatry 75(suppl. 2): ii43–ii50.
    Rezza A, Skah S, Roche C et al. (2010) The overexpression of the putative gut stem cell marker Musashi‐1 induces tumorigenesis through Wnt and Notch activation. Journal of Cell Science 123: 3256–3265.
    Richard S, Vogel G, Huot ME et al. (2008) Sam68 haploinsufficiency delays onset of mammary tumorigenesis and metastasis. Oncogene 27: 548–556.
    Riggi N, Cironi L, Suva ML and Stamenkovic I (2007) Sarcomas: genetics, signalling, and cellular origins. Part 1: the fellowship of TET. Journal of Pathology 213: 4–20.
    Ruggero D, Montanaro L, Ma L et al. (2004) The translation factor eIF‐4E promotes tumor formation and cooperates with c‐Myc in lymphomagenesis. Nature Medicine 10: 484–486.
    Sreedharan J, Blair IP, Tripathi VB et al. (2008) TDP‐43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319: 1668–1672.
    Torchia EC, Boyd K, Rehg JE, Qu C and Baker SJ (2007) EWS/FLI‐1 induces rapid onset of myeloid/erythroid leukemia in mice. Molecular and Cellular Biology 27: 7918–7934.
    Ule J and Darnell RB (2006) RNA binding proteins and the regulation of neuronal synaptic plasticity. Current Opinion in Neurobiology 16: 102–110.
    Ward AJ, Rimer M, Killian JM, Dowling JJ and Cooper TA (2010) CUGBP1 overexpression in mouse skeletal muscle reproduces features of myotonic dystrophy type 1. Human Molecular Genetics 19: 3614–3622.
    Wendel HG, Silva RL, Malina A et al. (2007) Dissecting eIF4E action in tumorigenesis. Genes & Development 21: 3232–3237.
    Wheeler TM, Sobczak K, Lueck JD et al. (2009) Reversal of RNA dominance by displacement of protein sequestered on triplet repeat RNA. Science 325: 336–339.
    Workman E, Saieva L, Carrel TL et al. (2009) A SMN missense mutation complements SMN2 restoring snRNPs and rescuing SMA mice. Human Molecular Genetics 18: 2215–2229.
 Further Reading
    Abu‐Baker A and Rouleau GA (2007) Oculopharyngeal muscular dystrophy: recent advances in the understanding of the molecular pathogenic mechanisms and treatment strategies. Biochimica et Biophysica Acta 1772: 173–185.
    Bardoni B, Davidovic L, Bensaid M and Khandjian EW (2006) The fragile X syndrome: exploring its molecular basis and seeking a treatment. Expert Reviews in Molecular Medicine 8: 1–16.
    Bielli P, Busa R, Paronetto MP and Sette C (2011) The RNA‐binding protein Sam68 is a multifunctional player in human cancer. Endocrine‐Related Cancer 18: R91–R102.
    Bolognani F and Perrone‐Bizzozero NI (2008) RNA‐protein interactions and control of mRNA stability in neurons. Journal of Neuroscience Research 86: 481–489.
    Cleveland DW and Rothstein JD (2001) From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nature Reviews Neuroscience 2: 806–819.
    Darnell JC, Mostovetsky O and Darnell RB (2005) FMRP RNA targets: identification and validation. Genes, Brain and Behavior 4: 341–349.
    Hsieh AC, Truitt ML and Ruggero D (2011) Oncogenic AKTivation of translation as a therapeutic target. British Journal of Cancer 105: 329–336.
    Leehey MA and Hagerman PJ (2012) Fragile X‐associated tremor/ataxia syndrome. Handbook of Clinical Neurology 103: 373–386.
    Richard S (2010) Reaching for the stars: Linking RNA binding proteins to diseases. Advances in Experimental Medicine and Biology 693: 142–157.
    Riggi N, Suva ML and Stamenkovic I (2009) Ewing's sarcoma origin: from duel to duality. Expert Review of Anticancer Therapy 9: 1025–1030.
    Van Meerbeke JP and Sumner CJ (2011) Progress and promise: the current status of spinal muscular atrophy therapeutics. Discovery medicine 12: 291–305.

Related Sub-Topics:

Neurobiology of Disease | Basic Cell Biology, Protein, RNA and DNA | Mutational Mechanisms of Genetic Disease | Cancer Genetics
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Implications of RNA‐binding Proteins for Human Diseases
 
How to Cite close
Lukong, Kiven E, and Fatimy, Rachid El(May 2012) Implications of RNA‐binding Proteins for Human Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023866]