Circular RNAs: Key Regulators in the Cell

The presence of circRNAs was first reported in 1979. However, their significance was not fully appreciated until the development of advanced sequencing technologies in the late 2000s. These technologies enabled the comprehensive identification of circRNAs across diverse species, revealing their abundance and potential roles.

History of the discovery and development of circRNAs. | Representative milestone events leading to the discovery and development of circRNAs are enumerated in the figure

Structure and Formation

Unlike linear RNAs, circRNAs are characterized by a closed circular loop formed by a covalent linkage between their 5' and 3' ends. This unique structure arises from a non-canonical splicing event termed back-splicing, where a downstream exon joins with an upstream exon instead of the usual linear order. Several mechanisms can regulate back-splicing, influencing circRNA biogenesis, abundance, and ultimately, their function.

Schematic representation of splicing events leading to the generation of circRNA. (a) The canonical splicing machinery conventionally generates normal mRNA. (b) Exonic circular RNA (circRNA) is generated through noncanonical splicing (backsplicing) through the unique 'head-to-tail' joining of the 5 0 splice site (5 0 ss, donor site) to a 3 0 splice site (3 0 ss, acceptor site). RNA-binding proteins (RBPs) or transacting factors can bridge two flanking introns close together. The introns are then removed to form a circRNA. (c) Reverse complementary sequences (purple arrows) in Intron1 and Intron3 can pair and bring the 5 0 ss of Exon3 close to 3 0 ss of Exon2, promote circularization of Exon2 and Exon3 with a retained intron, and form an exon–intron circRNA (EIciRNA). In addition, backsplicing in combination with canonical splicing may lead to the formation of circRNA with Exon2 and Exon3 only. (d) The circular intronic RNA (ciRNA) is derived from the lariat intron excised from pre-mRNA by canonical splicing machinery and depends on the presence of consensus RNA sequences (yellow bars) to avoid debranching of the lariat intron to form stable ciRNAs. The red and blue dotted lines indicate linear and head-to-tail backsplicing, respectively.

Functional Diversity

CircRNAs exhibit a remarkable range of functions within the cell. Here are some of their well-established roles:

  • MicroRNA Sponges: CircRNAs can act as sponges for microRNAs (miRNAs). By containing binding sites for miRNAs, circRNAs competitively sequester them, preventing them from downregulating their target genes. This allows circRNAs to indirectly regulate gene expression by modulating miRNA activity.
  • Protein Binding and Scaffolding: CircRNAs can interact with various proteins, including RNA-binding proteins and translation initiation factors. This interaction can influence protein function, localization, or even promote protein translation directly from the circRNA itself, although the latter is still under investigation.
  • Transcriptional Regulation: Recent evidence suggests circRNAs can modulate gene transcription by directly interacting with DNA or RNA polymerase II. This adds another layer of complexity to how gene expression is controlled within the cell.

The biological functions of circRNAs. a. circRNAs as miRNA sponges or decoys. For example, in Acute myeloid leukemia (AML), circMFN2 stimulates cell proliferation by sponging miR-20a-5p and protecting target mRNAs from miRNA-dependent degradation. b. circRNAs as protein recruiters. As illustrated, the FLI1 exonic circular RNA recruits methylcytosine dioxygenase TET1 to the promoter region of its host gene. Besides, in lymphoblastic lymphoma (LBL), circAPC decreases the cell viability and impairs DNA synthesis by inactivating Wnt/β-catenin signaling via interacting with TET1. c. circRNAs as protein function enhancers. circRNAs enhance the function of the RNA polymerase II (Pol II) complex containing U1 snRNP and other essential proteins. d. circRNAs as protein scaffolds. circRNAs can act as protein scaffolds and facilitate the colocalization of enzymes and their substrates to influence the reaction kinetics. e. circRNAs as protein sponges or decoys. circRNAs may function as sponges or decoys for proteins and indirectly regulate RBPs-dependent functions. f. circRNAs as translation templates. circRNAs with internal ribosome entry site (IRES) elements and AUG sites may be translated under certain circumstances, giving rise to unique peptides.

CircRNAs and Disease

The involvement of circRNAs in various cellular processes has led researchers to investigate their potential roles in disease development. Misregulation of circRNA expression has been linked to several diseases, including cancer, neurological disorders, and cardiovascular diseases.

For example, specific circRNAs have been shown to either promote or suppress tumor formation. Understanding the disease-specific functions of circRNAs could pave the way for the development of novel therapeutic strategies. By targeting circRNA biogenesis, function, or interaction with other molecules, researchers hope to manipulate gene expression patterns for therapeutic benefit.

Circular RNAs have been associated with various diseases. CircRNAs have been found to play important roles in diseases, including diabetes, cardiovascular diseases, age-related diseases, osteoarthritis, cancer, stress, viral diseases, and others.

Conclusion

The discovery of circRNAs has opened a new chapter in our understanding of gene regulation. These fascinating molecules exhibit remarkable structural and functional diversity, acting as miRNA sponges, protein scaffolds, and potential modulators of transcription. Their involvement in various diseases highlights their potential as novel therapeutic targets. As research in this field continues to advance, circRNAs are poised to become key players in unraveling the intricate mechanisms of cellular regulation and disease development.

Learn more about Circular RNA Immunity in this video:

 


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Circular RNAs: Key Regulators in the Cell
Gen store May 27, 2024
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