Something for You RNA World Enthusiasts

There is a paper in last week's Science that describes a proofreading mechanism in prokaryotic (i.e. bacterial) RNA Polymerase, the enzyme responsible for transcribing DNA into RNA. When RNA Pol incorporates the wrong base into a growing RNA, the enzyme moves two steps back and cleaves the dinucleotide fragment (the mismatched DNA-RNA base pair plus the preceding pair DNA-RNA pair).

So far that's OK. RNA Pol can correct mistakes and thus can transcribe with increased fidelity etc. But the cool part is that the data from this paper supports a model where the mismatched nucleotide participates in the RNA cleavage reaction. So the active site of RNA polymerase's proofreading activity ... is RNA!

Now why is this an important point? And what does this have to do with the RNA world?

Well let's look at the central dogma:

DNA => RNA => protein

This concept lies at the center of all biology. If someone asked you to summarize all known biological activity in one line, the central dogma is what you would tell them. The most conserved genes all deal with these processes (DNA => RNA, RNA=>protein). Well if this core idea was the center of the biology of all known organisms, and it's steps are performed by the products of the most conserved genes, well then you would expect that these enzymes may reveal something about the ancestral cell and it's biochemistry.

So who is this ancestor? It is widely thought that our ancestor was a self copying molecule. To perform this task, the first molecule must contain enzymatic activity (i.e. copying activity) AND the serves as a template for its copy (i.e. template activity). The only molecule known to potentially encapsulate these two functions is RNA. You see RNA can both carry genetic information AND act as an enzyme. It can be copied and potentially can copy. This evades the chicken egg problem for life to occur de novo. Our anscestral cells are thought to have evolved from this "RNA world", so the most basic cellular functions may have retained RNA world components.

So lets get back to the central dogma.

When it comes to the RNA => protein step, most of the core processes are performed by ribozymes (i.e. RNA molecules that act as enzymes). Some of these ribozymes and RNA based co-factors are well known ... the ribosome, tRNA etc. But how about the DNA => RNA step? Until now it was thought that this step was performed exclusively by a protein based enzyme. But this RNA based proofreading activity changes all that. This paper demonstrates that RNA Polymerase is partially a ribozyme. This ribozyme activity may be a remnant of the ancestral RNA polymerase from the RNA world. This ribozyme may at some stage passed though an RNA-protein hybrid (just like the ribosome) and in fact most of the RNA part was eventually replaced by protein based enzyme. In the end the only part of the original ribozyme left was the catalytic core of the proofreading activity. This catalytic core was dependent on the transcribed RNA itself and had a neat auto activation (cleavage is activated by the actual mismatch). It was hard to replace this catalytic core with proteinaceous components and so it was conserved and we still have it with us today. Every step in the central dogma is mediated in part by RNA.

Very cool.

Ref:
Nikolay Zenkin, Yulia Yuzenkova, and Konstantin Severinov
Transcript-Assisted Transcriptional Proofreading
Science (2006) 313:518-520

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Intersting stuff, thanks for directing my attention to it.

Well let's look at the central dogma:

DNA => RNA => protein

This concept lies at the center of all biology.

OK, this is for teaching purposes, so I won't point out that there are known exceptions to the central dogma; reverse transcriptase, RNA viruses...

Getting on the RNA World angle, the addition of DNA to the mix is though to be the last step of the RNA-Protein-DNA triumvarate, so the fact that RNApol contains mostly protein is not all that troubling.

By somnilista, FCD (not verified) on 10 Aug 2006 #permalink

OK, this is for teaching purposes, so I won't point out that this version of the central dogma (i.e., DNA => RNA => protein), though ubiquitous in biology textbooks, isn't equivalent to the version articulated by Crick (i.e., transfer of sequence information between nucleic acids and proteins is unidirectional). After almost 50 years, there are no known exceptions to Crick's CD (maybe, after we understand prions better, we'll have an exception in hand).

By bob koepp (not verified) on 21 Aug 2006 #permalink

Yes the famous triangular vector diagram. To me this version of the central dogma lists all possible information flow. However the very first depiction of the central dogma list how most information flows inside of living cells. The central dogma (as I depict it) was conceived (I believe) by Brenner when he worked with Crick. It was their best guess at how DNA transferred information to protein, thus the mRNA hypothesis. The updated version does not convey the same idea - it focuses on the exceptions.