MadSci Network: Genetics

Re: How does a cell 'know' what exons to use?

Date: Thu May 21 15:34:28 1998
Posted By: Michael Onken, Grad Student, Wash U
Area of science: Genetics
ID: 894549876.Ge

Splicing of mRNA is a very interesting field which has shaken the "Central Dogma", DNAÆRNAÆ Protein, but not in the way that you think. (Actually, scientists shun dogma, since it contradicts the bases of empircism - I'm still not sure where the term "Central Dogma" came from since it's been disputed for over 30 years.) In fact, the information on how genes are spliced is contained on the DNA at the Intron/Exon Boundaries. This information is copied, along with the gene, by RNA polymerase to the hnRNA from which the introns are removed to form mRNA. The consensus Intron/Exon Boundaries are:

5'                                                                3'
AG|GURAGU-------------------------------YNYYRAY------- --------(Y)12NYAG|R
splice donor                     lariat site         splice acceptor

Where puRine can be A or G, pYrimidine can be C or U, aNy can be A, C, G or U, and the underlined bases are the ends of the exons (the dashes are intervening sequences; introns can be many kilobases in size). There is a lot of variability in these sites except for the bases in bold which cannot be changed and are essential for splicing to occur.

Splicing is carried out by small, nuclear RNA particles (snRNP's, "snirps") which bind to the splice sites and excise the intron. Notice these are RNA particles not proteins! (Actually, mammalian snRNP's contain several proteins that catalyze the splicing reactions, however studies from several labs have demonstrated that the RNA portions of the snRNP's can function in the absence of protein, though more slowly.) The snRNP's involved in splicing all have a high uracil (U) content, and so they are named U1 - U6 . Each snRNP binds to a portion of the intron, and pulls the domains together to form a spliceosome, which carries out the actual cutting and pasting (these last two links are great animations of snRNP's, and worth seeing).

The snRNP's are members of a growing group of RNA molecules called Ribozymes, all of which have enzymatic activity similar to protein enzymes. Other ribozymes of interest here are the Group I and Group II self-extracting introns found in many protists. These introns can fold themselves into their own snRNP and cut themselves out of the hnRNA. These discoveries make DNA look like the poor cousin of RNA, since it is at the mercy of enzymes and ribozymes which decide the fate of the genes.

But before getting too caught up in the wonders of RNA, I should point out that in eukaryotes, all enzymes and ribozymes depend on the DNA genome for their own production, just as DNA depends on proteins and RNA for its replication. So there is really a dynamic interdependency among the three which requires each to be present for the other two to work in higher organisms.

A much more thorough discussion is available in Genes VI by Benjamin Lewin.

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