RBPs: Post-Transcriptional Regulators with Therapeutic Potential

RBPs: Orchestrators of Post-Transcriptional Fate

Following RNA polymerase II-mediated transcription, RBPs bind to specific sequences on pre-mRNA and mature mRNA, influencing their subsequent processing and function. This intricate regulatory network governs various aspects of RNA metabolism:

Major regulatory mechanisms of RBPs in breast cancer. including (A) miRNA processing; (B) selective splicing; (C) RNA stabilization and RNA degradation; (D) selective polyadenylation; (E) subcellular localization; (F) translation. The schematic diagram lists the RBPs involved in the regulatory mechanisms of breast cancer that appear in the article.

  • Alternative Splicing Modulation: RBPs regulate alternative splicing, a process that generates protein diversity from a single pre-mRNA transcript by modulating exon inclusion or exclusion. Here, an RBP can bind to specific splicing regulatory elements on the pre-mRNA, influencing which exons are included in the final mature mRNA.
  • Nucleocytoplasmic Transport Facilitation: Specific RBPs function as chaperones, facilitating the export of mature mRNA from the nucleus to the cytoplasm, a prerequisite for translation. These RBPs interact with export receptors in the nucleus, allowing the mature mRNA to pass through the nuclear envelope and reach the cytoplasm for protein synthesis.
  • mRNA Stability Control: RBP binding can impact mRNA stability. Some RBPs stabilize transcripts by protecting them from degradation by RNAse enzymes, while others recruit factors that promote mRNA decay. Depending on the bound RBP, the mRNA can be shielded from degradation enzymes or flagged for decay by other cellular proteins.
  • Subcellular mRNA Localization: RBPs can target specific mRNAs to distinct subcellular compartments, ensuring protein production occurs at the precise location within the cell. Certain RBPs contain targeting sequences that direct specific mRNAs to organelles like the mitochondria or endoplasmic reticulum.
  • Translational Regulation: RBPs can directly or indirectly regulate mRNA translation into proteins by influencing ribosome recruitment or interacting with translation initiation factors. RBPs can bind to the 5' untranslated region (UTR) of the mRNA, influencing ribosome binding or interacting with proteins involved in translation initiation.

Schematic diagram showing the extensive role of RBPs in various posttranscriptional processes at different locations in eukaryotic cells. The circled number indicates the process in which RBPs are involved. RBPs are major players in splicing pre-mRNAs into mature mRNAs in the nucleus, which are then exported into the cytoplasm by various other RBPs. Depending upon whether RBPs are bound to pre-mRNA or mRNA to form a RNP complex, RNPs are classified as hnRNPs or mRNPs, respectively. In addition, RBPs are responsible for the localization of mRNAs to distinct subcellular compartments such as the mitochondria. In the cytoplasm, RBPs are also involved in governing the stability of transcripts by binding the substrate RNAs, and in controlling the translation of mRNAs into corresponding protein products. Often, multiple RBPs can bind to a single RNA at one or more locations giving rise to a plethora of combinatorial possibilities at every step of posttranscriptional control. For this reason, RBPs have been found to be playing a major role in the cause of several disorders due to changes in regulation they bring about at posttranscriptional level.

Recent Advancements in RBP Function

Research continues to shed light on the multifaceted roles of RBPs:

  • Cellular Differentiation and Development: RBPs meticulously orchestrate gene expression programs essential for proper cellular differentiation and development. Disruptions in RBP function are linked to various human diseases, highlighting their critical role in maintaining cellular homeostasis.
  • Stem Cell Regulation: RBPs play a pivotal role in regulating the delicate balance between stem cell self-renewal and differentiation. Dysregulation of RBP activity has been implicated in stem cell-related disorders.
  • Immune Response Modulation: RBPs modulate the expression of genes critical for immune function. Aberrant RBP activity can contribute to autoimmune diseases and immune deficiencies.

RBPs as Therapeutic Targets: A New Frontier

The pivotal role of RBPs in gene regulation makes them promising therapeutic targets for various diseases. Researchers are exploring strategies to:

  • Modulating RBP Activity: Small molecule drugs or gene editing techniques could be used to activate or inhibit specific RBPs, correcting gene expression imbalances associated with disease. For instance, a small molecule drug could be designed to disrupt the interaction between an RBP and its RNA target, thereby influencing gene expression.
  • Disrupting RBP-RNA Interactions: Molecules designed to disrupt the interaction between RBPs and disease-associated RNA targets hold therapeutic potential for cancers and other disorders. These molecules could be antisense oligonucleotides that bind to the RNA target and prevent RBP binding.

Strategies that are being applied to target RBPs for cancer therapeutics. Small-molecules can be designed to inhibit the interaction of RBP with an RNA, suppress RBP's enzymatic activity, block RBP post-translationalmodification (PTM), or induce RBP degradation. The Peptides-based strategy can be designed to hinder the RBP associationwith its functional partner (s). The oligonucleotide-based strategies include ASO, siRNA, and Aptamer, which can either mediate RBP mRNA degradation or inhibit RBP-RNA interaction. In addition, two potential strategies are shown, natural/artificial circular RNAs- or CRISPR-based approaches. Circular RNAs can be designed to bind RBDs of RBPs and compete out target RNAs. CRISPR based approaches can be used to create oncogenic RBP knockout/knockin (to correct cancer-specific mutation in RBP or RBP binding sites). RISC, RNA-induced silencing complex.

Conclusion

RBPs emerge as essential regulators of post-transcriptional gene expression, impacting diverse aspects of RNA metabolism. Continued research on their functions and RNA interactions promises to provide deeper insights into human health and disease. The potential to modulate RBP activity or target RBP-RNA interactions opens new avenues for developing novel therapeutic strategies.


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RBPs: Post-Transcriptional Regulators with Therapeutic Potential
Gen store May 24, 2024
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