Posted by Oliver Stockert
There are two main types of snoRNAs that each have their own structure, function, and purpose. The two types are H/ACA box and C/D box snoRNAs. You may have heard of sequence “boxes” in regards to proteins or RNA before; it just means a section of the sequence is genetically conserved to make snoRNAs function and bind with a high level of specificity. Figure 1 outlines the H/ACA boxes and the C/D boxes on each type of snoRNA. The boxes represent an important parts of the sequences that all C/D box or H/ACA box snoRNAs contain that helps them carry out their roles.
Fig. 1. A diagram showing the two different types of snoRNAs and their secondary structures including (C/D)/(H/ACA) box sequences and locations. This figure is adopted from Swiatowy and Jagodzinski. 2018.
The main job of H/ACA box snoRNAs is to modify part of the nucleotides in other RNAs, giving them the power to alter how another RNA is functioning in the cell.
C/D box and H/ACA box snoRNAs both have very important rolls in the cell and in RNA modification, but from here forward we are going to focus only on C/D box snoRNAs. C/D box snoRNAs mainly modify ribosomal RNAs by methylating them. This occurs in a series of steps. First, the snoRNA attaches to a protein called a methyltransferase, which has the ability to methylate a nearby rRNA. Then the attached snoRNA “finds” the rRNA and allows the fibralin to methylate with increased specificity (See Figure 2). The snoRNA usually binds to a whole bunch of proteins, that forms a snoRNP complex that works together to find RNAs of interest, unfold them to allow access to the nucleotide sequence, and perform modifications. SnoRNAs also have many other functions in the body.
Figure 2. Both snoRNA and proteins are necessary for snoRNP to find, bind, unfold, and modify mRNA. (Figure made by author).
Now, you might be wondering, where do snoRNAs even come from? Let’s get into the biogenesis, or process of creation within a cell, of snoRNAs. You may have heard about introns, exons, and mRNA processing before, here are the main ideas: In eukaryotic cells, introns are pieces in mRNA that are excised from the mRNA that will eventually be translated. The process of removal of introns (unwanted regions) from exons (mRNA regions that we want to translate into protein) is a part mRNA processing called splicing, shown in Figure 3B. Some of the introns are just degraded by the exosome, but others are protected from the exosome by associating themselves with big clunky proteins. Some of these introns that are protected from degradation are precursors to snoRNAs. These RNAs are able to escape the exosome by folding into a double stranded RNA (dsRNA) and associating with snoRNP proteins, shown in Figure 3E. These introns are not just extra unwanted junk in between the exons! They have a specialized and evolved sequence that can fold into a snoRNA and interact with other macromolecules, like other RNAs or proteins.
Figure 3. Timeline of the snoRNA biogenesis and its formation with proteins to form the snoRNP complex. This figure is adopted from C/D‐box snoRNAs form methylating and non‐methylating ribonucleoprotein complexes: Old dogs show new tricks by Falaleeva M. et al. 2017.
SnoRNA 116, also called SNORD116, is a C/D box snoRNA, that has important roles in the modification of proteins in the serotonin receptor system. In a “normal” brain, the snoRNA is transcribed along with serotonin receptor proteins. The intron that becomes this snoRNA lies between exons that will be translated into serotonin receptor proteins. They both get transcribed simultaneousl, which means that there are equal amounts of exons that encode the proteins AND introns that form the snoRNA. Because the snoRNAs are present in equal amounts as the exons, they are very efficient at modifying the processed mRNA and being present whenever the mature mRNA is.
Disease and human health comes into play when someone is missing the part of the DNA that encodes for the intron that contains the snoRNA sequence. When the snoRNA is not present as a result of this genetic difference, it can not modify the serotonin system. This changes the way the proteins of the system do their job. Deletion of this snoRNA, along with a few others in a similar area, has a strong correlation with a condition, called Prader Willi, where the activity of the serotonin receptor system is altered. It arises from an inability to receive the satisfying feeling that serotonin produces when you eat and are full. As a result of the hyperphagia, many Prader Willi patients develop obesity or diabetes. In addition to this problem, the syndrome has other symptoms that have connections to the serotonin receptor system.
Overall, snoRNAs are very important in modifying ribosomal and messenger RNA. When the introns that contain the sequence for the snoRNA are not present in a genome, there can be large variations in how RNAs are modified and function in the serotonin receptor system. When this occurs there can be genetic differences like Prader Willi that cause problems with the function of brain cells. SnoRNAs are really interesting and have so much relevance to human health and the world around us. What’s your favorite RNA?
Sources:
Falaleeva M, Welden J, Duncan M, and Stamm S. 2017. C/D‐box snoRNAs form methylating and non‐methylating ribonucleoprotein complexes: Old dogs show new tricks. BioEssays
Swiatowy W, and Jagodzinski P. 2018. Molecules derived from tRNA and snoRNA: Entering the degradome pool. Biomedicine and Pharmacotherapy 108:36-42.
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