Protein Sequestration As a Normal Function of Long Noncoding RNAs and a Pathogenic Mechanism of RNAs Containing Nucleotide Repeat Expansions

Overview

Journal Hum Genet

Specialty Genetics

Date 2017 May 10

PMID 28484853

Citations 20

Authors

Ginny R Morriss

Thomas A Cooper

Affiliations

Soon will be listed here.

Abstract

An emerging class of long noncoding RNAs (lncRNAs) function as decoy molecules that bind and sequester proteins thereby inhibiting their normal functions. Titration of proteins by lncRNAs has wide-ranging effects affecting nearly all steps in gene expression. While decoy lncRNAs play a role in normal physiology, RNAs expressed from alleles containing nucleotide repeat expansions can be pathogenic due to protein sequestration resulting in disruption of normal functions. This review focuses on commonalities between decoy lncRNAs that regulate gene expression by competitive inhibition of protein function through sequestration and specific examples of nucleotide repeat expansion disorders mediated by toxic RNA that sequesters RNA-binding proteins and impedes their normal functions. Understanding how noncoding RNAs compete with various RNA and DNA molecules for binding of regulatory proteins will provide insight into how similar mechanisms contribute to disease pathogenesis.

Citing Articles

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References

Jin P, Duan R, Qurashi A, Qin Y, Tian D, Rosser T . Pur alpha binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndrome. Neuron. 2007; 55(4):556-64. PMC: 1994817. DOI: 10.1016/j.neuron.2007.07.020. View

Pickard M, Williams G . The hormone response element mimic sequence of GAS5 lncRNA is sufficient to induce apoptosis in breast cancer cells. Oncotarget. 2016; 7(9):10104-16. PMC: 4891107. DOI: 10.18632/oncotarget.7173. View

Yum K, Wang E, Kalsotra A . Myotonic dystrophy: disease repeat range, penetrance, age of onset, and relationship between repeat size and phenotypes. Curr Opin Genet Dev. 2017; 44:30-37. PMC: 5447468. DOI: 10.1016/j.gde.2017.01.007. View

Rudnicki D, Holmes S, Lin M, Thornton C, Ross C, Margolis R . Huntington's disease--like 2 is associated with CUG repeat-containing RNA foci. Ann Neurol. 2007; 61(3):272-82. DOI: 10.1002/ana.21081. View

Brouwer J, Willemsen R, Oostra B . The FMR1 gene and fragile X-associated tremor/ataxia syndrome. Am J Med Genet B Neuropsychiatr Genet. 2008; 150B(6):782-98. PMC: 4320942. DOI: 10.1002/ajmg.b.30910. View

Krawczyk M, Emerson B . p50-associated COX-2 extragenic RNA (PACER) activates COX-2 gene expression by occluding repressive NF-κB complexes. Elife. 2014; 3:e01776. PMC: 4017649. DOI: 10.7554/eLife.01776. View

Cleary J, Ranum L . Repeat-associated non-ATG (RAN) translation in neurological disease. Hum Mol Genet. 2013; 22(R1):R45-51. PMC: 3782068. DOI: 10.1093/hmg/ddt371. View

Liu W, Ikeda Y, Hishikawa N, Yamashita T, Deguchi K, Abe K . Characteristic RNA foci of the abnormal hexanucleotide GGCCUG repeat expansion in spinocerebellar ataxia type 36 (Asidan). Eur J Neurol. 2014; 21(11):1377-86. DOI: 10.1111/ene.12491. View

Miller J, Urbinati C, Stenberg M, Byrne B, Thornton C, Swanson M . Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy. EMBO J. 2000; 19(17):4439-48. PMC: 302046. DOI: 10.1093/emboj/19.17.4439. View

10.

Wang E, Cody N, Jog S, Biancolella M, Wang T, Treacy D . Transcriptome-wide regulation of pre-mRNA splicing and mRNA localization by muscleblind proteins. Cell. 2012; 150(4):710-24. PMC: 3428802. DOI: 10.1016/j.cell.2012.06.041. View

11.

Dijkstra J, Alexander D . The " NF-ĸ B interacting long noncoding RNA" ( NKILA) transcript is antisense to cancer-associated gene PMEPA1. F1000Res. 2015; 4:96. PMC: 4431381. DOI: 10.12688/f1000research.6400.1. View

12.

Roberts T, Morris K, Wood M . The role of long non-coding RNAs in neurodevelopment, brain function and neurological disease. Philos Trans R Soc Lond B Biol Sci. 2014; 369(1652). PMC: 4142028. DOI: 10.1098/rstb.2013.0507. View

13.

Hogan P, Chen L, Nardone J, Rao A . Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 2003; 17(18):2205-32. DOI: 10.1101/gad.1102703. View

14.

Pettersson O, Aagaard L, Andrejeva D, Thomsen R, Jensen T, Damgaard C . DDX6 regulates sequestered nuclear CUG-expanded DMPK-mRNA in dystrophia myotonica type 1. Nucleic Acids Res. 2014; 42(11):7186-200. PMC: 4066779. DOI: 10.1093/nar/gku352. View

15.

Qian M, Yang X, Li Z, Jiang C, Song D, Yan W . P50-associated COX-2 extragenic RNA (PACER) overexpression promotes proliferation and metastasis of osteosarcoma cells by activating COX-2 gene. Tumour Biol. 2015; 37(3):3879-86. DOI: 10.1007/s13277-015-3838-8. View

16.

Michalowski S, Miller J, Urbinati C, Paliouras M, Swanson M, Griffith J . Visualization of double-stranded RNAs from the myotonic dystrophy protein kinase gene and interactions with CUG-binding protein. Nucleic Acids Res. 1999; 27(17):3534-42. PMC: 148598. DOI: 10.1093/nar/27.17.3534. View

17.

Thornton C . Myotonic dystrophy. Neurol Clin. 2014; 32(3):705-19, viii. PMC: 4105852. DOI: 10.1016/j.ncl.2014.04.011. View

18.

Kearse M, Todd P . Repeat-associated non-AUG translation and its impact in neurodegenerative disease. Neurotherapeutics. 2014; 11(4):721-31. PMC: 4391382. DOI: 10.1007/s13311-014-0292-z. View

19.

Kalsotra A, Xiao X, Ward A, Castle J, Johnson J, Burge C . A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart. Proc Natl Acad Sci U S A. 2008; 105(51):20333-8. PMC: 2629332. DOI: 10.1073/pnas.0809045105. View

20.

Reddy K, Zamiri B, Stanley S, Macgregor Jr R, Pearson C . The disease-associated r(GGGGCC)n repeat from the C9orf72 gene forms tract length-dependent uni- and multimolecular RNA G-quadruplex structures. J Biol Chem. 2013; 288(14):9860-9866. PMC: 3617286. DOI: 10.1074/jbc.C113.452532. View