Structure and Function of Circular RNA (circRNA)

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Circular RNA (circRNA) is a fascinating and enigmatic class of RNA molecules that has been increasingly recognized for its unique structural and functional characteristics. Unlike the more well-known linear RNA, circRNA forms a closed-loop structure, which distinguishes it from the traditional linear RNA molecules in cells.

Definition of circular RNA (circRNA):

Circular RNA, as the name suggests, is a type of RNA that forms a closed-loop structure without 5′ and 3′ ends. This circular conformation is primarily created through a process called back-splicing, where a downstream 3′ splice site joins with an upstream 5′ splice site, leading to the formation of a circular molecule. This unique structure endows circRNAs with exceptional stability and resistance to exonucleases, contributing to their prolonged presence in cells.

Structure of circular RNA (circRNA):

Circular RNA (circRNA) has gained prominence due to its unique structural characteristics, challenging traditional views of RNA architecture. The closed-loop structure of circular RNA (circRNA), formed through back-splicing, presents a distinctive molecular framework that contributes to their stability and functional diversity within cellular processes.

Circular Structure:

  • Closed-Loop Formation: Unlike linear RNA molecules, circRNAs exhibit a closed-loop structure, lacking the conventional 5′ and 3′ ends.
  • Back-Splicing: The circular conformation results from a process called back-splicing, where a downstream 3′ splice site joins with an upstream 5′ splice site, creating a continuous circular molecule.
  • Stability: The absence of free ends imparts remarkable stability to circRNAs, rendering them resistant to exonucleases and contributing to their prolonged presence in cells.

Biological Origins:

  • Splicing Machinery Involvement: CircRNA biogenesis is intricately linked to the cellular splicing machinery.
  • Genomic Regions: Back-splicing can occur in various genomic regions, including exons, introns, and intergenic regions.
  • Dynamic Regulatory Processes: The precise regulatory factors and cellular conditions governing circRNA biogenesis are subjects of ongoing research, reflecting the dynamic nature of circRNA biology.

Structural Diversity:

  • Exonic CircRNAs: Comprise exons in a circular arrangement.
  • Intronic CircRNAs: Retain intronic sequences in their circular form.
  • Exonic-Intronic CircRNAs: Combine both exonic and intronic regions.
  • Multifaceted Roles: Structural diversity hints at the multifaceted roles and regulatory capabilities of circRNAs within cellular processes.

Functional Implications:

  • Molecular Sponges: CircRNAs can act as molecular sponges, sequestering microRNAs and modulating their regulatory activity.
  • Protein Translation: Some circRNAs have the potential to be translated into proteins, challenging the conventional dichotomy of coding and non-coding RNAs.
  • RNA-Binding Proteins Interaction: CircRNAs interact with RNA-binding proteins, influencing diverse cellular pathways.

If you want to know about the other RNAs then read the article: Structure and Function of Long Non-Coding RNAs (lncRNAs).

Function of Circular RNA (circRNA):

Circular RNA (circRNA) has emerged as pivotal players in cellular processes, contributing to the intricate web of gene regulation and expression. Their diverse functions challenge traditional views of RNA molecules and underscore the complexity of molecular biology.

MicroRNA Sponges:

  • Sequestration of MicroRNAs: The circular RNA (circRNA)can act as molecular sponges by binding to and sequestering microRNAs.
  • Inhibition of MicroRNA Activity: This interaction modulates the activity of microRNAs, preventing them from suppressing the expression of target genes.
  • Fine-Tuning Gene Expression: By regulating microRNA activity, circRNAs contribute to the fine-tuning of gene expression levels in cells.

Interaction with RNA-Binding Proteins:

  • Modulation of Protein Function: CircRNAs can interact with RNA-binding proteins, influencing their functions.
  • Regulation of Cellular Pathways: These interactions impact various cellular pathways, adding an additional layer of complexity to gene regulation.
  • Diverse Cellular Processes: CircRNAs play roles in processes such as cell proliferation, differentiation, and apoptosis through their interactions with RNA-binding proteins.

Translation into Functional Proteins:

  • Challenging the Coding/Non-Coding Paradigm: Contrary to the traditional view of non-coding RNAs, some circRNAs have been found to be translated into functional proteins.
  • Expanding the Functional Repertoire: This discovery expands the functional repertoire of circRNAs, blurring the lines between coding and non-coding RNA molecules.
  • Potential Therapeutic Targets: CircRNAs with translation potential open new avenues for therapeutic interventions targeting specific proteins associated with diseases.

Cellular Implications:

  • Regulation of Cell Proliferation: CircRNAs are implicated in the regulation of cell proliferation, influencing the rate at which cells divide and replicate.
  • Involvement in Cell Differentiation: CircRNAs play roles in cell differentiation processes, contributing to the development of specialized cell types.
  • Impact on Apoptosis: The influence of circRNAs on apoptosis highlights their involvement in programmed cell death, a critical aspect of cellular homeostasis.

Disease Pathogenesis:

  • Association with Cancer: Dysregulation of circRNAs is observed in various cancers, implicating them in the pathogenesis of these diseases.
  • Link to Neurodegenerative Disorders: CircRNAs are also implicated in neurodegenerative disorders, adding to the growing understanding of their role in disease mechanisms.
  • Diagnostic and Therapeutic Potential: The identification of disease-associated circRNAs offers diagnostic potential and novel therapeutic targets for various medical conditions.

Examples of Examples of circular RNA (circRNA):

Circular RNA (circRNA) represent a fascinating class of molecules with a diverse array of functions. As our understanding of these circular transcripts deepens, several notable examples have been identified, showcasing the versatility and complexity of circular RNA (circRNA) roles within cellular processes.

Cdr1as (CiRS-7):

  • MicroRNA Sponge: Cdr1as is a well-known circRNA that acts as a sponge for miR-7, a microRNA involved in regulating various cellular functions.
  • Regulation of Gene Expression: By sequestering miR-7, Cdr1as indirectly regulates the expression of miR-7 target genes, influencing processes such as cell proliferation and apoptosis.

HIPK3:

  • Regulation of Cell Growth: HIPK3 circRNA has been identified as a regulator of cell growth by interacting with miR-124.
  • Inhibition of miR-124: HIPK3 circRNA inhibits the activity of miR-124, thereby affecting the expression of its target genes and influencing cell growth and differentiation.

EWSR1:

  • Promotion of Oncogenic Features: In certain cancer types, the EWSR1 gene generates a circRNA that promotes oncogenic features.
  • Interaction with RNA-Binding Proteins: This circRNA interacts with RNA-binding proteins, contributing to the dysregulation of cellular pathways associated with cancer progression.

circ-Foxo3:

  • Regulation of Cell Cycle: circ-Foxo3 functions as a tumor suppressor by inhibiting cell cycle progression.
  • Interference with Cell Cycle Proteins: Through interactions with cyclin-dependent kinase 2 (CDK2) and p21, circ-Foxo3 interferes with the cell cycle, preventing uncontrolled cell proliferation.

Sry (Sex-determining Region Y):

  • Testis Development: The Sry gene produces a circRNA that plays a role in testis development.
  • Interaction with RNA-Binding Proteins: Sry circRNA interacts with RNA-binding proteins, contributing to the regulation of genes involved in male sex determination.

circMbl:

  • Regulation of Splicing: circMbl, derived from the muscleblind (MBL) gene, regulates the splicing of its linear mRNA counterpart.
  • Modulation of MBL Activity: By interacting with MBL protein, circMbl modulates the splicing activity of MBL, influencing alternative splicing patterns in the cell.

This distinctive feature has sparked considerable interest among researchers, as circular RNA (circRNA) plays pivotal roles in various biological processes, offering a novel dimension to our understanding of gene expression and regulation.

Frequently Asked Questions(FAQ):

1. What is Circular RNA (circRNA)?

Circular RNA (circRNA) is a type of RNA molecule characterized by a covalently closed circular structure. Unlike linear RNAs, which have distinct 5′ and 3′ ends, circRNAs form a continuous loop with no free ends.

2. How are circRNAs formed?

CircRNAs are generated through a process known as back-splicing, where a downstream splice donor site joins with an upstream splice acceptor site, resulting in the formation of a circular structure. This circularization can occur during splicing of precursor mRNA (pre-mRNA) transcripts.

3. What is the structure of circRNA?

CircRNAs have a covalently closed loop structure, making them resistant to exonuclease-mediated degradation. They lack free ends and are more stable than linear RNAs. CircRNAs can be single-stranded or double-stranded, and they may contain internal RNA modifications.

4. What are the functions of circRNA?

CircRNAs have diverse functions in gene regulation, including:
Acting as miRNA sponges: CircRNAs can sequester microRNAs (miRNAs), preventing them from binding to their target mRNAs and thereby modulating gene expression.
Interacting with RNA-binding proteins (RBPs): CircRNAs can bind to RBPs and regulate their activities, influencing RNA processing, translation, and localization.
Serving as templates for translation: Some circRNAs have been found to contain open reading frames (ORFs) and can be translated into proteins or peptides, contributing to cellular functions.

5. How are circRNAs different from linear RNAs?

CircRNAs differ from linear RNAs primarily in their structure and stability:
Structure: CircRNAs form closed-loop structures, whereas linear RNAs have distinct 5′ and 3′ ends.
Stability: CircRNAs are more resistant to degradation by exonucleases due to their circular structure, making them more stable than linear RNAs.

6. How are circRNAs detected and analyzed?

CircRNAs can be detected and analyzed using various experimental techniques, including:
RNA sequencing (RNA-seq): High-throughput sequencing methods can identify circRNAs based on their unique back-splicing junctions.
Reverse transcription-polymerase chain reaction (RT-PCR): Specific primers spanning the back-splicing junctions can be used to amplify circRNAs for detection and quantification.
Computational methods: Bioinformatics tools and algorithms are available to predict and analyze circRNA sequences and structures from genomic and transcriptomic data.