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May232011

RNA pushing the limits: Challenging Central Dogma

Most people I talk to haven’t taken a biology class since high school – but try to reach back into the shadowy depths of your inner-high school student and remember the “Central Dogma” of molecular biology - this dogma is what biology is built on, this is geneticist’s and molecular biologist’s bread and butter:

DNA encodes bases (ATCG’s) that will be transcribed into messenger RNA (mRNA), this mRNA will be the template that will be translated into proteins.



Today a paper in Science challenges this theory – and who better to challenge the stable ground that biologists walk on than RNA. Sticking to the high school theme, RNA is molecular biology’s “bad boy”, the sexy boundary-pushing bad boy that breaks all the rules in all of the right ways.

Mingyao Li et al. have found that RNA has challenged the Central Dogma, showing that in human cells many proteins do not match their underlying DNA sequences. They found in the 27 human subjects looked at, that over 28,000 events occurred where the RNA sequences did not match that of the DNA. Using mass spectrometry to identify the proteins translated from the RNA, they found that the proteins do not correspond to the DNA sequences in which they originated.

There have been known reasons why RNA does not match DNA and these have been shown to be very rare and could not be seen widespread in a human cell population. Here they have found this RNA editing occurs much more frequently than anyone had ever thought.

To put things in perspective, these RNA edits may be a source of human genetic diversity that had previously been unknown – and this diversity may explain why different people are more susceptible to different diseases.

ResearchBlogging.org

Li M, Wang IX, Li Y, Bruzel A, Richards AL, Toung JM, & Cheung VG (2011). Widespread RNA and DNA Sequence Differences in the Human Transcriptome. Science (New York, N.Y.) PMID: 21596952

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Reader Comments (9)

Would this be related at all to the intron/exon gene splicing process? The introns are spliced out of the RNA sequence, so could these RNA edits arise from the same process?

May 23, 2011 | Unregistered CommenterTripp

Hey, this is definitely not a violation of central dogma, which only argues that DNA goes to RNA, but RNA never goes back to DNA. However, it is awfully cool...

May 23, 2011 | Unregistered CommenterSteve

There are always little caveats in biology. Hell, even "STOP" codons aren't always treated as translational stopping points and can actually encode specific amino acids.
alized tRNA
Srinivasan et al. "Pyrrolysine Encoded by UAG in Archaea: Charging of a UAG-Decoding Specialized tRNA" Science 24 May 2002.

Similar note you would be interested in:
These guys made an RNA-dependent RNA polymerase using just RNA (a ribozyme) from random RNA sequences, and selected for ones that could consistently replicate RNA.
http://www.sciencemag.org/content/332/6026/209.full
Wochner et al. "Ribozyme-Catalyzed Transcription of an Active Ribozyme."Science 8 April 2011

May 24, 2011 | Unregistered CommenterAnonymous

Excellent tip Anonymous! I wrote a blog post about that a few months ago right here:

http://www.smallerquestions.org/2011/02/what-came-first-chickens-rna-or.html

May 24, 2011 | Unregistered CommenterBrooke N.

Hey Steve, interesting point, but not accurate - here is a review over Central Dogma from Cell:

Cell. 2011 Feb 18;144(4):480-97.
Revisiting the central dogma one molecule at a time.
Bustamante C, Cheng W, Mejia YX.
Source

May 24, 2011 | Unregistered CommenterBrooke N.

Tripp: Yes, "splicing" is a form of post-transcriptional modification, but splicing removes known sequences from RNA with known mechanisms. Splicing is carried out by the "spliceosome", a complex of small nuclear ribonucleoprotiens, where introns are excised from the nascant RNA to produce mRNA that will be translated. The new mechanism they're characterizing is carried out by an unknown protein & mechanism. In addition, these modifications are to the spliced exonic regions.

May 24, 2011 | Unregistered CommenterBrooke N.

Hi, Brooke.
I think Steve is right, and that does not violate central dogma. it's about the direction of the information flow. reverse transcriptase caused the dogma to be rewritten IIRC, but RNA editing is not changing it.
the review you are citing is on proteins/machinery involved in 'central dogma processes' - replication/transcription/translation, but does not redefine it in any way.

May 26, 2011 | Unregistered Commentermigg

Hey Migg,

On second thought I do think Steve is right in his idea of Central Dogma. He's right in that there is directionality in Central Dogma. However, I do think this is a violation of central dogma if you believe that central dogma states that the sequence of bases encoded in DNA determines the sequence of amino acids that makes up the corresponding proteins.

That review is more based on machinery, but allows one to understand the idea of Central Dogma.

Let me find a better review!!
Thanks!
Brooke

May 26, 2011 | Unregistered CommenterBrooke N.

I have put a picture up on here: http://imgur.com/ZJqcR

This shows the "possible" (solid arrows) and "impossible" (dotted arrows) - Since DNA cannot go directly into protein, you would only go one other route, DNA to RNA to protein - and if you have DNA to RNA and then a modification of the RNA to make a specific protein, you can complicate the simple diagram that was proposed in 1958 by Watson & Crick. I guess it was poor wording to say "Challenged", I think a better way to present this new paper is "modify". Modify because you're adding a step, it is not as simple as this DNA makes this protein with an RNA intermediate, it's this DNA makes this RNA, this RNA is modified and creates a totally different protein.

May 26, 2011 | Unregistered CommenterBrooke N.

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