Image: Based upon conserved snoRNA sequence elements, this large population of guide RNAs has been divided into two major families designated the box C/D and the box H/ACA snoRNAs. The primary function of the box C/D snoRNAs is to guide 2′-O-methylation of targeted rRNA nucleotides while the box H/ACA snoRNAs direct the conversion of specific uridine residues to pseudouridine.
Scientists have discovered unexpected functions of small nucleolar RNAs (snoRNAs) that explain the cause of some genetic diseases and cancers. However, it is not clear how the change in snoRNA expression could lead to these diseases. Using RNA sequencing and molecular biology techniques, researchers found snoRNAs not only modify ribosomes, but can also regulate alternative splicing. Through this second function, they regulate protein function and inhibit the generation of wrong protein variants. This explains the role of snoRNAs in human diseases, as upon their loss the formation of wrong protein variants can no longer be prevented.
The loss of small nucleolar RNAs is associated with a number of diseases, including Prader-Willi syndrome, characterized by an unstoppable appetite, and several forms of cancers: smoldering multiple myeloma, breast and prostate cancer. Also, genetic duplications of some snoRNAs could play a role in autism. However, it is not clear how the change in snoRNA expression could lead to these diseases.
To make proteins that function in cells, a “photocopy” of the genetic information stored in the DNA is made, ie precursor messenger RNA (pre-mRNA). From these precursor molecules the important information containing the blueprint for proteins has to be extracted through splicing, where introns, are cut out and the remaining exons, are pasted together to generate messenger RNA (mRNA).
Importantly, most mammalian pre-mRNAs are multi-intronic, that can be spliced out in different combinations. Therefore, an important major mechanism that is at work for building complex organisms and organs is alternative splicing, in which by different combinations of alternative splicing a single gene can code for multiple proteins. The misregulation of the alternative splicing process contributes to numerous diseases, including cancer.
The RNA that makes mRNA, the coding RNA, contain the information to make proteins, which form the body, but most RNAs are non-coding, and contain regulatory information controlling the expression of genes. Among the non-coding RNA, the about 250 snoRNAs – one of the longest-studied RNAs – are a class of small RNA molecules that primarily guide chemical modifications of other RNAs. These are shown to control the modification of ribosomes that read mRNAs to make proteins.
In mechanistic studies, they also showed short synthetic RNAs could be used as a substitute for the missing snoRNAs. This could point to a possible therapy for genetic hyperphagia (a condition that causes extreme hunger or appetite) and some forms of cancer.
“This research helps us to understand the unexpected dual role of snoRNAs in gene regulation. It further points to the important role played by small non-coding RNAs in alternative splicing, which is a major contributor to the diversity of the human proteome, and defects in which result in numerous diseases. With further research in this area we may be able to design new therapies against human diseases,” said Prof. Ruth Sperling.
http://new.huji.ac.il/en/article/31166
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