EMBO Trinucleotide Expansion Disease Conference 

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Dr. John Hancock, c/o Mrs Rosemary Bowen, MRC Clinical Sciences Centre,

Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN

20th January 1998

Dear Dr. Hancock,

I here apply to attend the EMBO workshop in April.  From our recent email correspondence I gather that there might be a few places for non-EMBO applicants at the Trinucleotide Expansion Disease conference. Actually, as you will see from the enclosed CV, I am originally from an EMBO country although no longer a resident. I attach an abstract of some of our current work which has implications for the question as to why the trinucleotides were there in the first place.

                        Sincerely, Donald Forsdyke


PURINE LOADING 0F EBNA-1 mRNA AVOIDS SENSE-ANTISENSE "COLLISIONS": IMPLICATIONS FOR TRINUCLEOTIDE EXPLANSION DISEASE. A. D. Cristillo, T. P. Lillicrap and D. R. Forsdyke. Dept. Biochem., Queen's University, Kingston, Ontario, Canada K7L3N6

   In the 1960's Szybalski showed that mRNA-synonymous strands of DNA have purine-rich clusters, and Chargaff presented his second parity rule that, to a close approximation, %A=%T and %C=%G for single DNA strands. We report that small deviations from the rule (%R>%Y in mRNA-synonymous strands) allow determination of transcription direction for the majority of genes in many species (Bell & Forsdyke, unpublished work; Dang et al. 1998, Biochem. Cell Biol. in press). Purine clusters in an mRNA correspond to the loop domains of potential stem-loop structures, which, by virtue of being enriched with non-complementary bases, should avoid loop-loop "kissing" interactions with other mRNAs in the same cell.  However, most genes of CG-rich viruses with a high commitment to latency (HTLV-1, Epstein-Barr) disobey the transcription direction rule (%Y>%R). Thus, the viruses have pyrimidine clusters in the loop domains of potential RNA stem-loop structures. By "driving on the wrong side of the road" they invite sense-antisense RNA "collisions" with host mRNAs, thus triggering the interferon response and increasing MHC protein expression. However, the only gene transcribed during the "EBNA-1 only program" of viral latency is "polite" (%R>%Y). This purine-loading requires the protein to carry a non-functional (GlyAla) simple-sequence domain, reflecting an expansion of certain purine-rich codons. We propose that many trinucleotide expansions reflect pressure to purine-load RNAs, to avoid triggering MHC presentation of self-proteins. The advantage of this adaptation is unfortunately countermanded by the tendency towards hyperexpansion with adverse consequences for the solubility of the encoded protein (see "Entropy-driven protein self-aggregation as the basis for self/not-self discrimination in the crowded cytosol" J. Biol. Sys. (1995) 3, 273-287).

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Last edited on 06 Sep 2010 by Donald Forsdyke. For some years the conference abstracts were displayed at Hancock's webpage.