Structural insights of RNaseP helps scientists understand tRNA processing

A new wave of discoveries in the RNA field occurred in early November. Today the BIoA is highlighting updates made to ribonuclease P (RNaseP).  Why is this molecule so important? Why do scientists study this particular RNA enzyme? And how is this enzyme related at all with human health? 

Well to start off RNaseP is unlike any other enzyme because it operates on RNA molecules and the catalytic component of the enzyme is itself an RNA. Of course, there is one other enzyme that does this, and that is the ribosome! Since, Dr. Sidney Altman’s discovery that RNaseP is required for the processing of the 5′ leader sequence of tRNAs, scientists have shown RNaseP is essential for the proper transcription of a swath of noncoding RNA genes transcribed by RNA pol III, such as tRNA, rRNAs, and snRNAs.

The other fascinating finding is that RNaseP is found everywhere, in every cell, and in every organism. Such ultra conservation of a molecule indicates not only a crucial biological importance for RNaseP, it also implicates RNaseP as a living fossil of the much touted “RNA-world” that existed around the time life began on planet Earth. 

Apart from being an RNA fossil, why should I care about RNaseP?  If it is so ubiquitous, then why should I target it for any type of medicinal purposes… Well for one thing, dumb chemotherapies such as cisplatin that target the most ubiquitous biological process of DNA replication works quite well, despite some the toxic pitfalls (see our previous LinkedIn post on that concept). And secondly, scientists love to go after ubiquitous targets, but do not like to admit it. TP53, the protein that codes for P53, is a very distributed transcription factor expressed nearly everywhere, yet millions of dollars have been spent developing P53-based therapies. So the rationale is just in my mind for scientists to go after RNaseP as a drug target.

So which diseases? Well RNaseP enzymatically cleaves RNA, so why not develop therapies using RNaseP against RNA-mediated diseases such as herpes and influenza. In fact that is what is going on right now. Approximately 80,000 people will die of influenza this year, while ~45,000 women will die of breast cancer. So there is a clear clinical rationale for developing new and innovative RNA-based therapies for a number of these chronic or acute infections. 

Why do we care about RNaseP today? Well in Science, Lan et. al., reported some updated crystal structures of RNaseP from yeast (both in it’s isolated state, and in complex with tRNA). An old saying in the scientific community is “structure-function”. Essentially if you understand how an enzyme is built via structure, then you can develop smarter drugs that disrupt an interfered function. The study by Lan et. al., shows pretty convincingly that all forms of RNaseP (called ribozymes) share an RNA-based, substrate induced catalytic mechanism for the processing of pre-RNAs. In eukaryotes, the pre-RNA is the substrate, the RNaseP enzyme is controlled or regulated by proteins in the cell, and the catalytic activity of RNAseP is still RNA-based. 

So much like receptor tyrosine kinase inhibitors that are used in cancer therapy because they interfere with the enzymatic activity of the protein, so to should RNA-based therapies be developed so as to interfere with RNaseP activity for the betterment human health.

 

See references article below-

http://bit.ly/2SzoqQE

 

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Written by Brian D. Adams, President, CEO, Director of Research, The Brain Institute of America

 

– Let’s End This!

 

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