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Circular RNAs pp 53–63Cite as

Circular RNAs Biogenesis in Eukaryotes Through Self-Cleaving Hammerhead Ribozymes

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1087))

Abstract

Circular DNAs are frequent genomic molecules, especially among the simplest life beings, whereas circular RNAs have been regarded as weird nucleic acids in biology. Now we know that eukaryotes are able to express circRNAs, mostly derived from backsplicing mechanisms, and playing different biological roles such as regulation of RNA splicing and transcription, among others. However, a second natural and highly efficient pathway for the expression in vivo of circRNAs has been recently reported, which allows the accumulation of abundant small (100–1000 nt) non-coding RNA circles through the participation of small self-cleaving RNAs or ribozymes called hammerhead ribozymes. These genome-encoded circRNAs with ribozymes seem to be a new family of small and nonautonomous retrotransposable elements of plants and animals (so-called retrozymes), which will offer functional clues to the biology and evolution of circular RNA molecules as well as new biotechnological tools in this emerging field.

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Abbreviations

circRNA:

circular RNA

HHR:

hammerhead ribozyme

LTR:

long terminal repeat

PBS:

primer binding site

PPT:

polypurine tract

RT:

retrotranscriptase

TSD:

target site duplication

References

  1. Lasda E, Parker R (2014) Circular RNAs: diversity of form and function. RNA 20(12):1829–1842

    Article  CAS  Google Scholar 

  2. Salzman J, Gawad C, Wang PL et al (2012) Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PloS One 7(2):e30733

    Article  CAS  Google Scholar 

  3. Jeck WR, Sorrentino JA, Wang K et al (2013) Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA 19(2):141–157

    Article  CAS  Google Scholar 

  4. Wang PL, Bao Y, Yee MC et al (2014) Circular RNA is expressed across the eukaryotic tree of life. PloS One 9(6):e90859

    Article  Google Scholar 

  5. Ashwal-Fluss R, Meyer M, Pamudurti NR et al (2014) circRNA biogenesis competes with pre-mRNA splicing. Mol Cell 56(1):55–66

    Article  CAS  Google Scholar 

  6. Memczak S, Jens M, Elefsinioti A et al (2013) Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495(7441):333–338

    Article  CAS  Google Scholar 

  7. Hansen TB, Jensen TI, Clausen BH et al (2013) Natural RNA circles function as efficient microRNA sponges. Nature 495(7441):384–388

    Article  CAS  Google Scholar 

  8. Talhouarne GJ, Gall JG (2014) Lariat intronic RNAs in the cytoplasm of Xenopus tropicalis oocytes. RNA 20(9):1476–1487

    Article  CAS  Google Scholar 

  9. De la Peña M, Cervera A (2017) Circular RNAs with hammerhead ribozymes encoded in eukaryotic genomes: the enemy at home. RNA Biol 14(8):985–991

    Article  Google Scholar 

  10. Cervera A, Urbina D, de la Peña M (2016) Retrozymes are a unique family of non-autonomous retrotransposons with hammerhead ribozymes that propagate in plants through circular RNAs. Genome Biol 17(1):135

    Article  Google Scholar 

  11. De la Peña M, Garcia-Robles I, Cervera A (2017) The hammerhead ribozyme: a long history for a short RNA. Molecules 22(1):78–89

    Article  Google Scholar 

  12. Kruger K, Grabowski PJ, Zaug AJ et al (1982) Self-splicing RNA: autoexcision and autocyclization of the ribosomal RNA intervening sequence of Tetrahymena. Cell 31(1):147–157

    Article  CAS  Google Scholar 

  13. Guerrier-Takada C, Gardiner K, Marsh T et al (1983) The RNA moiety of ribonuclease P is the catalytic subunit of the enzyme. Cell 35(3 Pt 2):849–857

    Article  CAS  Google Scholar 

  14. Gilbert W (1986) The RNA world. Nature 319:618

    Article  Google Scholar 

  15. Crick FH (1968) The origin of the genetic code. J Mol Biol 38(3):367–379

    Article  CAS  Google Scholar 

  16. Orgel LE (1968) Evolution of the genetic apparatus. J Mol Biol 38(3):381–393

    Article  CAS  Google Scholar 

  17. Woese CR (1968) The fundamental nature of the genetic code: prebiotic interactions between polynucleotides and polyamino acids or their derivatives. Proc Natl Acad Sci U S A 59(1):110–117

    Article  CAS  Google Scholar 

  18. Steitz TA, Moore PB (2003) RNA, the first macromolecular catalyst: the ribosome is a ribozyme. Trends Biochem Sci 28(8):411–418

    Article  CAS  Google Scholar 

  19. Ferre-D’Amare AR, Scott WG (2010) Small self-cleaving ribozymes. Cold Spring Harb Perspect Biol 2(10):a003574

    PubMed  PubMed Central  Google Scholar 

  20. Valadkhan S, Manley JL (2001) Splicing-related catalysis by protein-free snRNAs. Nature 413(6857):701–707

    Article  CAS  Google Scholar 

  21. Winkler W, Nahvi A, Breaker RR (2002) Thiamine derivatives bind messenger RNAs directly to regulate bacterial gene expression. Nature 419(6910):952–956

    Article  CAS  Google Scholar 

  22. Mojica FJ, Diez-Villasenor C, Garcia-Martinez J et al (2005) Intervening sequences of regularly spaced prokaryotic repeats derive from foreign genetic elements. J Mol Evol 60(2):174–182

    Article  CAS  Google Scholar 

  23. Fire A, Xu S, Montgomery MK et al (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391(6669):806–811

    Article  CAS  Google Scholar 

  24. Prody GA, Bakos JT, Buzayan JM et al (1986) Autolytic processing of dimeric plant virus satellite RNA. Science 231(4745):1577–1580

    Article  CAS  Google Scholar 

  25. Hutchins CJ, Rathjen PD, Forster AC et al (1986) Self-cleavage of plus and minus RNA transcripts of avocado sunblotch viroid. Nucleic Acids Res 14(9):3627–3640

    Article  CAS  Google Scholar 

  26. Buzayan JM, Gerlach WL, Bruening G (1986) Non-enzymatic cleavage and ligation of RNAs complementary to a plant virus satellite RNA. Nature 323:349–353

    Article  CAS  Google Scholar 

  27. Kuo MY, Sharmeen L, Dinter-Gottlieb G et al (1988) Characterization of self-cleaving RNA sequences on the genome and antigenome of human hepatitis delta virus. J Virol 62(12):4439–4444

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Saville BJ, Collins RA (1990) A site-specific self-cleavage reaction performed by a novel RNA in Neurospora mitochondria. Cell 61(4):685–696

    Article  CAS  Google Scholar 

  29. Winkler WC, Nahvi A, Roth A et al (2004) Control of gene expression by a natural metabolite-responsive ribozyme. Nature 428(6980):281–286

    Article  CAS  Google Scholar 

  30. Roth A, Weinberg Z, Chen AG et al (2014) A widespread self-cleaving ribozyme class is revealed by bioinformatics. Nat Chem Biol 10(1):56–60

    Article  CAS  Google Scholar 

  31. Weinberg Z, Kim PB, Chen TH et al (2015) New classes of self-cleaving ribozymes revealed by comparative genomics analysis. Nat Chem Biol 11(8):606–610

    Article  CAS  Google Scholar 

  32. De la Peña M, Gago S, Flores R (2003) Peripheral regions of natural hammerhead ribozymes greatly increase their self-cleavage activity. EMBO J 22(20):5561–5570

    Article  Google Scholar 

  33. Khvorova A, Lescoute A, Westhof E et al (2003) Sequence elements outside the hammerhead ribozyme catalytic core enable intracellular activity. Nat Struct Biol 10(9):708–712

    Article  CAS  Google Scholar 

  34. Martick M, Scott WG (2006) Tertiary contacts distant from the active site prime a ribozyme for catalysis. Cell 126(2):309–320

    Article  CAS  Google Scholar 

  35. Przybilski R, Graf S, Lescoute A et al (2005) Functional hammerhead ribozymes naturally encoded in the genome of Arabidopsis thaliana. Plant Cell 17(7):1877–1885

    Article  CAS  Google Scholar 

  36. Ferbeyre G, Smith JM, Cedergren R (1998) Schistosome satellite DNA encodes active hammerhead ribozymes. Mol Cell Biol 18(7):3880–3888

    Article  CAS  Google Scholar 

  37. Rojas AA, Vazquez-Tello A, Ferbeyre G et al (2000) Hammerhead-mediated processing of satellite pDo500 family transcripts from Dolichopoda cave crickets. Nucleic Acids Res 28(20):4037–4043

    Article  CAS  Google Scholar 

  38. Epstein LM, Gall JG (1987) Self-cleaving transcripts of satellite DNA from the newt. Cell 48(3):535–543

    Article  CAS  Google Scholar 

  39. Martick M, Horan LH, Noller HF et al (2008) A discontinuous hammerhead ribozyme embedded in a mammalian messenger RNA. Nature 454(7206):899–902

    Article  CAS  Google Scholar 

  40. De la Peña M, Garcia-Robles I (2010) Ubiquitous presence of the hammerhead ribozyme motif along the tree of life. RNA 16(10):1943–1950

    Article  Google Scholar 

  41. Jimenez RM, Delwart E, Luptak A (2011) Structure-based search reveals hammerhead ribozymes in the human microbiome. J Biol Chem 286(10):7737–7743

    Article  CAS  Google Scholar 

  42. Perreault J, Weinberg Z, Roth A et al (2011) Identification of hammerhead ribozymes in all domains of life reveals novel structural variations. PLoS Comput Biol 7(5):e1002031

    Article  CAS  Google Scholar 

  43. Seehafer C, Kalweit A, Steger G et al (2011) From alpaca to zebrafish: hammerhead ribozymes wherever you look. RNA 17(1):21–26

    Article  CAS  Google Scholar 

  44. De la Peña M, Garcia-Robles I (2010) Intronic hammerhead ribozymes are ultraconserved in the human genome. EMBO Rep 11(9):711–716

    Article  Google Scholar 

  45. Hammann C, Luptak A, Perreault J et al (2012) The ubiquitous hammerhead ribozyme. RNA 18(5):871–885

    Article  CAS  Google Scholar 

  46. Garcia-Robles I, Sanchez-Navarro J, De la Peña M (2012) Intronic hammerhead ribozymes in mRNA biogenesis. Biol Chem 393(11):1317–1326

    Article  CAS  Google Scholar 

  47. Webb CH, Riccitelli NJ, Ruminski DJ et al (2009) Widespread occurrence of self-cleaving ribozymes. Science 326(5955):953

    Article  CAS  Google Scholar 

  48. Cervera A, De la Peña M (2014) Eukaryotic penelope-like retroelements encode hammerhead ribozyme motifs. Mol Biol Evol 31(11):2941–2947

    Article  CAS  Google Scholar 

  49. Eickbush DG, Eickbush TH (2010) R2 retrotransposons encode a self-cleaving ribozyme for processing from an rRNA cotranscript. Mol Cell Biol 30(13):3142–3150

    Article  CAS  Google Scholar 

  50. Ruminski DJ, Webb CH, Riccitelli NJ et al (2011) Processing and translation initiation of non-long terminal repeat retrotransposons by hepatitis delta virus (HDV)-like self-cleaving ribozymes. J Biol Chem 286(48):41286–41295

    Article  CAS  Google Scholar 

  51. Kennell JC, Saville BJ, Mohr S et al (1995) The VS catalytic RNA replicates by reverse transcription as a satellite of a retroplasmid. Genes Dev 9(3):294–303

    Article  CAS  Google Scholar 

  52. Gorinsek B, Gubensek F, Kordis D (2004) Evolutionary genomics of chromoviruses in eukaryotes. Mol Biol Evol 21(5):781–798

    Article  CAS  Google Scholar 

  53. Witte CP, Le QH, Bureau T et al (2001) Terminal-repeat retrotransposons in miniature (TRIM) are involved in restructuring plant genomes. Proc Natl Acad Sci U S A 98(24):13778–13783

    Article  CAS  Google Scholar 

  54. Gao D, Chen J, Chen M et al (2012) A highly conserved, small LTR retrotransposon that preferentially targets genes in grass genomes. PloS one 7(2):e32010

    Article  CAS  Google Scholar 

  55. Forster AC, Davies C, Sheldon CC et al (1988) Self-cleaving viroid and newt RNAs may only be active as dimers. Nature 334(6179):265–267

    Article  CAS  Google Scholar 

  56. Kalendar R, Tanskanen J, Chang W et al (2008) Cassandra retrotransposons carry independently transcribed 5S RNA. Proc Natl Acad Sci U S A 105(15):5833–5838

    Article  CAS  Google Scholar 

  57. Flores R, Grubb D, Elleuch A et al (2011) Rolling-circle replication of viroids, viroid-like satellite RNAs and hepatitis delta virus: variations on a theme. RNA Biol 8(2):200–206

    Article  CAS  Google Scholar 

  58. Jangam D, Feschotte C, Betran E (2017) Transposable element domestication as an adaptation to evolutionary conflicts. Trends Genet 33(11):817–831

    Article  CAS  Google Scholar 

  59. Salehi-Ashtiani K, Luptak A, Litovchick A et al (2006) A genomewide search for ribozymes reveals an HDV-like sequence in the human CPEB3 gene. Science 313(5794):1788–1792

    Article  CAS  Google Scholar 

  60. Chi YI, Martick M, Lares M et al (2008) Capturing hammerhead ribozyme structures in action by modulating general base catalysis. PLoS Biol 6(9):e234

    Article  Google Scholar 

  61. Dufour D, de la Peña M, Gago S et al (2009) Structure-function analysis of the ribozymes of chrysanthemum chlorotic mottle viroid: a loop-loop interaction motif conserved in most natural hammerheads. Nucleic Acids Res 37(2):368–381

    Article  CAS  Google Scholar 

  62. Gago S, De la Peña M, Flores R (2005) A kissing-loop interaction in a hammerhead viroid RNA critical for its in vitro folding and in vivo viability. RNA 11(7):1073–1083

    Article  CAS  Google Scholar 

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Funding

Funding for this work was provided by the Ministerio de Economía y Competitividad of Spain and FEDER funds (BFU2014-56094-P and BFU2017-87370-P).

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Authors and Affiliations

  1. IBMCP (CSIC-UPV), Valencia, Spain

    Marcos de la Peña

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  1. Marcos de la Peña
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Correspondence to Marcos de la Peña .

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Editors and Affiliations

  1. School of Life Science, Institute of Cardiovascular Sciences, Shanghai University, Shanghai, China

    Junjie Xiao

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de la Peña, M. (2018). Circular RNAs Biogenesis in Eukaryotes Through Self-Cleaving Hammerhead Ribozymes. In: Xiao, J. (eds) Circular RNAs. Advances in Experimental Medicine and Biology, vol 1087. Springer, Singapore. https://doi.org/10.1007/978-981-13-1426-1_5

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