RNA Splicing

A little about RNA splicing machinery: Possibly the most complex macromolecular machine in the cell

What is RNA splicing?

Many human genes (+-94%) contain exons (the DNA sequences that code for amino acids). These exons can be spliced together to form different types of proteins from a single gene.

How is it controlled?

Extensively and exquisitely controlled.

How common is it in humans?

Human Genes: Alternative Splicing Far More Common Than Thought

Quote:

ScienceDaily (Nov. 4, 2008) — Scientists have long known that it's possible for one gene to produce slightly different forms of the same protein by skipping or including certain sequences from the messenger RNA. Now, an MIT team has shown that this phenomenon, known as alternative splicing, is both far more prevalent and varies more between tissues than was previously believed.

Quote:

Two different forms of the same protein, known as isoforms, can have different, even completely opposite functions. For example, one protein may activate cell death pathways while its close relative promotes cell survival. The researchers found that the type of isoform produced is often highly tissue-dependent. Certain protein isoforms that are common in heart tissue, for example, might be very rare in brain tissue, so that the alternative exon functions like a molecular switch. Scientists who study splicing have a general idea of how tissue-specificity may be achieved, but they have much less understanding of why isoforms display such tissue specificity, Burge said.

Thus, the same gene can result in different functions, depending on the functionality and control of the RNA splicing machinery.

Is it important?

Humans And Chimps Differ At Level Of Gene Splicing
Not only do we differ genetically, but the way the genes are processed differ.

What happens if the machinery malfunctions?

Quality control systems are in place.
RNA Biology Finding Makes Waves By Challenging Current Thinking

Quote:

ScienceDaily (Jan. 23, 2008) — Case Western Reserve University School of Medicine researcher Kristian E. Baker, Ph.D. challenges molecular biology's established body of evidence and widely-accepted model for nonsense-mediated messenger ribonucleic acid (mRNA) decay with a new study. With her collaborator, Ambro van Hoof, Ph.D. of The University of Texas Health Sciences Center, Baker directly tested the "faux 3' UTR" model and proved it could not explain how cells recognize and destroy deviant mRNA. This landmark discovery will redirect mRNA research and expand opportunities for new discoveries in understanding the cells' ability to protect itself from these potential errors.

Quote:

In all cells, including human, mRNA is a copy of the information carried by a gene on the DNA. Occasionally, mRNA contains errors that can make the information it carries unusable. Cells posses a remarkable mechanism to detect these aberrant mRNAs and eliminate them from the cell -- this process represents a very important quality control system for gene expression. "A significant amount of past research in this area of RNA biology has collected data to support the 'faux 3' UTR' model for mRNA quality control, and, as a result, has shaped present research directions in the field," said Baker. "Our recent findings preclude this explanation and will, undoubtedly, result in a rethinking by many as to how to experimentally approach this important cellular process." For decades researchers have been puzzled by cells' ability to differentiate between "normal" mRNA and those carrying certain types of mutations. mRNA transports DNA's genetic coding information to the sites of protein synthesis: ribosomes. Cells are able to identify mRNA carrying a mutation and prevent it from reaching the protein synthesis phase. Once identified, the cell destroys the abnormal, mutated mRNA. This naturally occurring process ensures malfunctioning proteins are not produced. Using a yeast model system, Baker's research offers a better understanding of this mRNA quality control process which closely mimics the process in human cells.

Present in yeast, primitive organisms.

But how prevalent is this kind of machinery?

Visualizing The Machinery Of mRNA Splicing

Quote:

ScienceDaily (Apr. 8, 2008) — Recent research at Yale provided a glimpse of the ancient mechanism that helped diversify our genomes; it illuminated a relationship between gene processing in humans and the most primitive organisms by creating the first crystal structure of a crucial self-splicing region of RNA.

Quote:

This work, published in Science, highlights a 16-year quest by Anna Marie Pyle, the William Edward Gilbert Professor of Molecular Biophysics & Biochemistry at Yale, and her research team into the nature of "group II" introns, a particular type of intron within gene transcripts that catalyzes its own removal during the maturation of RNA. Group II introns are found throughout nature, in all forms of living organisms. Although much has been learned about their structure and how they work through biochemical and computational analysis, until now there have been no high-resolution crystal structures available. The resulting images have provided both confirmation of the earlier work and new information on the three-dimensional structure of RNA and the mechanism of splicing. "One of the most exciting aspects of this work was that we did not need to do anything disruptive to these molecules to prepare them for structural analysis," said Pyle. "The molecules showed us their structure, their active site and their activity -- all in a natural state. We were even able to visualize their associated ions." According to Pyle, the crystal structure revealed some unexpected features -- showing two sections that were most implicated as key elements of the active site and strengthening a theory that the process of splicing in humans "shares a close evolutionary heritage" with ancient forms of bacteria.

Forms of this machinery present all the way down to bacteria.

Here is a video describing the process.