Characteristics of Circular RNAs Generated by Human Survival Motor Neuron Genes

Overview

Journal Cell Signal

Date 2020 Jun 20

PMID 32553550

Citations 12

Authors

Eric W Ottesen

Ravindra N Singh

Affiliations

Soon will be listed here.

Abstract

Circular RNAs (circRNAs) belong to a diverse class of stable RNAs expressed in all cell types. Their proposed functions include sponging of microRNAs (miRNAs), sequestration and trafficking of proteins, assembly of multimeric complexes, production of peptides, and regulation of transcription. Backsplicing due to RNA structures formed by an exceptionally high number of Alu repeats lead to the production of a vast repertoire of circRNAs by human Survival Motor Neuron genes, SMN1 and SMN2, that code for SMN, an essential multifunctional protein. Low levels of SMN due to deletion or mutation of SMN1 result in spinal muscular atrophy (SMA), a major genetic disease of infants and children. Mild SMA is also recorded in adult population, expanding the spectrum of the disease. Here we review SMN circRNAs with respect to their biogenesis, sequence features, and potential functions. We also discuss how SMN circRNAs could be exploited for diagnostic and therapeutic purposes.

Citing Articles

Transcriptome- and proteome-wide effects of a circular RNA encompassing four early exons of the spinal muscular atrophy genes.

Luo D, Ottesen E, Lee J, Singh R Sci Rep. 2024; 14(1):10442.

PMID: 38714739 PMC: 11076517. DOI: 10.1038/s41598-024-60593-7.

Transcriptome- and proteome-wide effects of a circular RNA encompassing four early exons of the spinal muscular atrophy genes.

Luo D, Ottesen E, Lee J, Singh R Res Sq. 2024; .

PMID: 38464174 PMC: 10925445. DOI: 10.21203/rs.3.rs-3818622/v1.

Sex Difference in Spinal Muscular Atrophy Patients - are Males More Vulnerable?.

Sun J, Harrington M, Porter B J Neuromuscul Dis. 2023; 10(5):847-867.

PMID: 37393514 PMC: 10578261. DOI: 10.3233/JND-230011.

The SMN Complex at the Crossroad between RNA Metabolism and Neurodegeneration.

Faravelli I, Riboldi G, Rinchetti P, Lotti F Int J Mol Sci. 2023; 24(3).

PMID: 36768569 PMC: 9917330. DOI: 10.3390/ijms24032247.

Brain-protective mechanisms of autophagy associated circRNAs: Kick starting self-cleaning mode in brain cells circRNAs as a potential therapeutic approach for neurodegenerative diseases.

Basri R, Awan F, Yang B, Awan U, Obaid A, Naz A Front Mol Neurosci. 2023; 15:1078441.

PMID: 36727091 PMC: 9885805. DOI: 10.3389/fnmol.2022.1078441.

References

Martin R, Gupta K, Ninan N, Perry K, Van Duyne G . The survival motor neuron protein forms soluble glycine zipper oligomers. Structure. 2012; 20(11):1929-39. PMC: 3519385. DOI: 10.1016/j.str.2012.08.024. View

Christiansen J, Kolte A, Hansen T, Nielsen F . IGF2 mRNA-binding protein 2: biological function and putative role in type 2 diabetes. J Mol Endocrinol. 2009; 43(5):187-95. DOI: 10.1677/JME-09-0016. View

Cartegni L, Krainer A . Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1. Nat Genet. 2002; 30(4):377-84. DOI: 10.1038/ng854. View

Fallini C, Rouanet J, Donlin-Asp P, Guo P, Zhang H, Singer R . Dynamics of survival of motor neuron (SMN) protein interaction with the mRNA-binding protein IMP1 facilitates its trafficking into motor neuron axons. Dev Neurobiol. 2013; 74(3):319-332. PMC: 3906212. DOI: 10.1002/dneu.22111. View

Singh N, Singh N, Androphy E, Singh R . Splicing of a critical exon of human Survival Motor Neuron is regulated by a unique silencer element located in the last intron. Mol Cell Biol. 2006; 26(4):1333-46. PMC: 1367187. DOI: 10.1128/MCB.26.4.1333-1346.2006. View

Aktas T, Ilik I, Maticzka D, Bhardwaj V, Pessoa Rodrigues C, Mittler G . DHX9 suppresses RNA processing defects originating from the Alu invasion of the human genome. Nature. 2017; 544(7648):115-119. DOI: 10.1038/nature21715. View

Singh N, Howell M, Androphy E, Singh R . How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy. Gene Ther. 2017; 24(9):520-526. PMC: 5623086. DOI: 10.1038/gt.2017.34. View

Sorek R, Lev-Maor G, Reznik M, Dagan T, Belinky F, Graur D . Minimal conditions for exonization of intronic sequences: 5' splice site formation in alu exons. Mol Cell. 2004; 14(2):221-31. DOI: 10.1016/s1097-2765(04)00181-9. View

Roca X, Krainer A, Eperon I . Pick one, but be quick: 5' splice sites and the problems of too many choices. Genes Dev. 2013; 27(2):129-44. PMC: 3566305. DOI: 10.1101/gad.209759.112. View

10.

Howell M, Singh N, Singh R . Advances in therapeutic development for spinal muscular atrophy. Future Med Chem. 2014; 6(9):1081-99. PMC: 4356243. DOI: 10.4155/fmc.14.63. View

11.

Singh N, Del Rio-Malewski J, Luo D, Ottesen E, Howell M, Singh R . Activation of a cryptic 5' splice site reverses the impact of pathogenic splice site mutations in the spinal muscular atrophy gene. Nucleic Acids Res. 2017; 45(21):12214-12240. PMC: 5716214. DOI: 10.1093/nar/gkx824. View

12.

Workman E, Veith A, Battle D . U1A regulates 3' processing of the survival motor neuron mRNA. J Biol Chem. 2013; 289(6):3703-12. PMC: 3916568. DOI: 10.1074/jbc.M113.538264. View

13.

Isken O, Maquat L . The multiple lives of NMD factors: balancing roles in gene and genome regulation. Nat Rev Genet. 2008; 9(9):699-712. PMC: 3711694. DOI: 10.1038/nrg2402. View

14.

Weishaupt J, Hyman T, Dikic I . Common Molecular Pathways in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Trends Mol Med. 2016; 22(9):769-783. DOI: 10.1016/j.molmed.2016.07.005. View

15.

Dudekula D, Panda A, Grammatikakis I, De S, Abdelmohsen K, Gorospe M . CircInteractome: A web tool for exploring circular RNAs and their interacting proteins and microRNAs. RNA Biol. 2015; 13(1):34-42. PMC: 4829301. DOI: 10.1080/15476286.2015.1128065. View

16.

Li Z, Huang C, Bao C, Chen L, Lin M, Wang X . Exon-intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol. 2015; 22(3):256-64. DOI: 10.1038/nsmb.2959. View

17.

Chi B, OConnell J, Iocolano A, Coady J, Yu Y, Gangopadhyay J . The neurodegenerative diseases ALS and SMA are linked at the molecular level via the ASC-1 complex. Nucleic Acids Res. 2018; 46(22):11939-11951. PMC: 6294556. DOI: 10.1093/nar/gky1093. View

18.

Ashwal-Fluss R, Meyer M, Pamudurti N, Ivanov A, Bartok O, Hanan M . circRNA biogenesis competes with pre-mRNA splicing. Mol Cell. 2014; 56(1):55-66. DOI: 10.1016/j.molcel.2014.08.019. View

19.

Wirth B, Karakaya M, Kye M, Mendoza-Ferreira N . Twenty-Five Years of Spinal Muscular Atrophy Research: From Phenotype to Genotype to Therapy, and What Comes Next. Annu Rev Genomics Hum Genet. 2020; 21:231-261. DOI: 10.1146/annurev-genom-102319-103602. View

20.

Workman E, Kalda C, Patel A, Battle D . Gemin5 Binds to the Survival Motor Neuron mRNA to Regulate SMN Expression. J Biol Chem. 2015; 290(25):15662-15669. PMC: 4505476. DOI: 10.1074/jbc.M115.646257. View