Introduction:
Post-transcriptional modifications (PTMs) are changes that occur to RNA molecules after transcription. These modifications can include the addition of chemical groups, the removal of certain nucleotides, or the modification of existing nucleotides.
PTMs can affect the stability, localization, and function of RNA molecules, and can play important roles in gene expression and regulation.
RNA processing is the term collectively used to describe the sequence of events through which the primary transcript from a gene acquires its mature form.
RNA processing dysregulation can have catastrophic consequences and has been linked to a variety of illnesses, including cancer and neurological disorders.
Steps:
Capping:
This PTM involves the addition of a modified nucleotide called a “cap” to the 5′ end of an mRNA molecule. The cap helps protect the mRNA from degradation and helps it interact with ribosomes during translation.
Fig: RNA Capping
Splicing:
This PTM involves the removal of non-coding segments of an mRNA molecule, called introns, and the joining together of the remaining coding segments, called exons. This process is necessary to produce a functional protein.
Fig: Gene Splicing
Polyadenylation:
This PTM involves the addition of a string of adenine nucleotides, called a poly(A) tail, to the 3′ end of an mRNA molecule. The poly(A) tail helps stabilize the mRNA and facilitates its transport out of the nucleus.
Fig: Polyadenylation
RNA editing:
This PTM involves the alteration of the nucleotide sequence of an RNA molecule through the addition, deletion, or substitution of individual nucleotides. RNA editing can occur at any point in the RNA molecule and can have a variety of functional consequences.
Covalent Modifications:
It occurs after transcription, which is the process of synthesizing RNA from a DNA template.
Methylation: This PTM involves the addition of a methyl group (-CH3) to specific nucleotides within an RNA molecule. Methylation can affect the stability, localization, or function of the RNA molecule.
Acetylation: This PTM involves the addition of an acetyl group (-COCH3) to specific amino acid residues within a protein or to specific nucleotides within an RNA molecule. Acetylation can affect the stability, localization, or function of the modified molecule.
Phosphorylation: This PTM involves the addition of a phosphate group (-PO4) to specific amino acid residues within a protein or to specific nucleotides within an RNA molecule. Phosphorylation can affect the stability, localization, or function of the modified molecule.
Ubiquitination: This PTM involves the addition of a ubiquitin molecule to a protein, which targets it for degradation by the proteasome. Ubiquitination can regulate the stability and function of a protein.
Regulations:
Enzymatic modification: Many PTMs are carried out by specific enzymes that are responsible for adding or removing specific chemical groups to or from specific nucleotides within the RNA molecule. These enzymes are highly specific and are often regulated at the transcriptional or translational level.
mRNA stability: The stability of an mRNA molecule can be affected by PTMs, such as the addition of a poly(A) tail or the methylation of specific nucleotides. The stability of an mRNA can influence its half-life and the amount of protein that is produced from it.
RNA-binding proteins: Many PTMs are facilitated by RNA-binding proteins that recognize specific sequences within the RNA molecule and modulate its stability, localization, or function. These proteins can act as positive or negative regulators of PTM.
Small RNA molecules: Small RNA molecules, such as microRNAs (miRNAs) and small interfering RNAs (siRNAs), can regulate PTMs by binding to specific sequences within the RNA molecule and inhibiting its stability or function.
Genetic and epigenetic factors: PTMs can also be influenced by genetic and epigenetic factors, such as DNA methylation and histone modification, which can affect the accessibility of specific sequences within the RNA molecule to PTM enzymes.
Environmental factors: External factors, such as temperature, pH, and the presence of specific chemicals, can also influence PTMs by affecting the activity of PTM enzymes or the stability of the RNA molecule.
RNA editing:
RNA editing is a type of post-transcriptional modification (PTM) that involves the alteration of the nucleotide sequence of an RNA molecule through the addition, deletion, or substitution of individual nucleotides. RNA editing can occur at any point within the RNA molecule and can have a variety of functional consequences.
RNA editing is carried out by a class of enzymes called adenosine deaminases that act on RNA (ADARs). ADARs recognize specific sequences within the RNA molecule and catalyse the conversion of adenine to inosine. RNA editing is regulated by a variety of mechanisms, including transcriptional and post-transcriptional regulation of ADARs and the availability of substrate nucleotides.
It is important for the proper functioning of many biological processes, including gene expression, protein synthesis, and immune responses. Dysregulation of RNA editing has been implicated in a number of diseases, including cancer, neurological disorders, and autoimmune diseases. RNA editing can occur through several mechanisms.
A-to-I editing:
This type of editing involves the conversion of adenine nucleotides to inosine nucleotides. Inosine is chemically similar to adenine, but it is recognized as a guanosine nucleotide by the ribosome during translation. A-to-I editing can alter the sequence of amino acids in a protein and can have regulatory effects on gene expression.
C-to-U editing:
This type of editing involves the conversion of cytosine nucleotides to uracil nucleotides. C-to-U editing can affect the stability or function of the RNA molecule.
G-to-A editing:
This type of editing involves the conversion of guanine nucleotides to adenine nucleotides. G-to-A editing can alter the secondary structure of the RNA molecule and can affect its stability or function.
RNA Transport from the Nucleus to the Cytoplasm:
RNA transport from the nucleus to the cytoplasm is the process by which RNA molecules are transported from the nucleus, where they are synthesized and processed, to the cytoplasm, where they can be translated into protein. This process is important for the proper regulation of gene expression and the function of cells.
In eukaryotic cells, the nucleus and cytoplasm are separated by the nuclear envelope, a double membrane that surrounds the nucleus. RNA molecules must pass through nuclear pore complexes (NPCs) in the nuclear envelope to enter or exit the nucleus. NPCs are large protein complexes that span the nuclear envelope and are selectively permeable, allowing only certain molecules to pass through.
RNA transport from the nucleus to the cytoplasm is mediated by proteins called transportins, which bind to specific sequences on the RNA molecule and interact with the NPC to facilitate transport through the nuclear envelope. The direction of transport (into or out of the nucleus) is determined by the presence of specific signals on the RNA molecule and the presence of regulatory proteins that bind to these signals.
RNA transport is regulated at multiple levels, including transcription, splicing, and export, and is important for the proper function of cells. Dysregulation of RNA transport has been implicated in various diseases, including cancer and neurodegenerative disorders.
Importance of PTM:
Post-transcriptional modifications (PTMs) of RNA molecules play important roles in a variety of biological processes, including gene expression, protein synthesis, and the regulation of RNA stability and localization.
Gene expression: PTMs can affect gene expression by influencing the stability, localization, or function of the RNA molecule. For example, the addition of a poly(A) tail to the 3′ end of an mRNA molecule can increase its stability and facilitate its transport out of the nucleus, leading to increased protein synthesis. On the other hand, the hydrolysis of an mRNA molecule can result in its degradation and a decrease in protein synthesis.
Protein synthesis: PTMs can also affect protein synthesis by modifying the sequence of amino acids in a protein. For example, A-to-I editing of an mRNA molecule can alter the sequence of amino acids in a protein, potentially changing its function.
RNA stability and localization: PTMs can also affect the stability and localization of an RNA molecule. For example, the addition of a poly(A) tail can increase the stability of an mRNA molecule, while methylation of specific nucleotides can affect its localization within the cell.
References:
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- Stojković, V. and Fujimori, D.G., 2015. Radical SAM-mediated methylation of ribosomal RNA. In Methods in enzymology (Vol. 560, pp. 355-376). Academic Press.