10.3: Origin and Functions of RNA

People initially believed that RNA only acted as an intermediate between the DNA code and the protein, however, in early 80s, the discovery of catalytic RNAs (ribozymes) expanded the perspective on what this molecule can actually do in living things. Sidney Altman and Thomas Cech discovered the first ribozyme, RNase P which is able to cleave off the head of tRNA. Self-splicing introns (group I introns) were also one of the first ribozymes that were discovered. They do not need any protein as catalysts to splice. Single or double stranded RNA also serves as the information storage and replication agent in some viruses.

The RNA World Hypothesis, proposed by Walter Gilbert in 1986, suggests that RNA was the precursor to modern life. It relies on the fact that RNA can have both information storage, and catalytic activity at the same time, both of which are fundamental characteristics of a living system. In short, the RNA World hypothesis says that, because RNA can have a catalytic role in cells and there is evidence that RNA can self-replicate without depending on other molecules, an RNA World is a plausible precursor of today’s DNA and protein based world. Although to this day, there are no natural self-replicating RNA found in vivo, self- replicating RNA molecules have been created in lab via artificial selection. For example, a chimeric construct of a natural ligase ribozyme with an in vitro selected template binding domain has been shown to be able to replicate at least one turn of an RNA helix. For this reason, Gilbert proposed RNA as a plausible origin for life. The theory suggests that through evolution, RNA has passed its information storage role to DNA, a more stable molecule and one less prone to mutation. RNA then assumed the role of intermediate between DNA and proteins, which took over some of RNA’s catalytic role in the cell. Thus, scientists sometimes refer to RNA as molecular fossils. Even though RNA has lost a lot of its information-storage functionality to DNA and its functional properties to proteins, RNA still plays an integral role in the living organisms. For instance, the catalytic portion of the ribosome i.e. the main functional part of the ribosomal complex consists of RNA. RNA also has regulatory roles in the cell, and basically serves as an agent for the cell to sense and react to the environment.

Riboswitches

Regulatory RNAs have different families, and one of the most important ones are riboswitches. Riboswitches are involved in different levels of gene regulation. In some bacteria, important regulations are done by simple RNA families. One example is the thermosensor in Listeria, a riboswitch that blocks the ribosomes at low temperature (since the hydrogen bonds are more stable). The RNA then forms a semi- double stranded conformation which does not bind to the ribosome and turns the ribosome off. At higher temperatures (37 C), the double strand opens up and allows ribosome to attach to a certain region in the riboswitch, making translation possible once again. Another famous Riboswitch is the adenine Riboswitch (and in general purine riboswitches) , which regulate protein synthesis. For example the ydhl mRNA which has a terminator stem at the end and blocks it from translation, but when the Adenine concentration in- creases in the cell, it binds to the mRNA and changes its conformation such that the terminator stem disappears.

microRNAs

There are other sorts of RNAs such as microRNAs, a more modern variant of RNA (relatively). Their discovery unveiled a novel non-protein layer of gene regulation (e.g. the EVF-2 and HOTAIR miRNAs). EVF-2 is interesting because its transcribed from an ultra conserved enhancer, and separates from the transcription string by forming a hairpin, and thereafter returns to the very same enhancer (along with a protein Dlx-2) and regulates its activity. HOTAIR RNA induces changes in chromatin state, and regulates the methylation of Histones, which in turn silences the HOX-D cluster.

Other types of RNA

We can also look at types of noncoding RNAs.

• piRNAs are the largest class of small non-coding RNA molecules in animals. They are primarily involved in the silencing of transposons, but likely have a lot of functions. They are also involved in epigenetic modications, and post-transcriptional gene silencing.
• lncRNAs are long transcripts produced that operate functionally as RNAs and are not translated into proteins. Many studies implicate lncRNAs in epigenetic modications, maybe acting as a targeting mechanism or as a molecular scaffold for Polycomb proteins. lncRNAs are likely to possess numerous functions, many are nuclear, many are cytoplasmic.