MRC Clinical Sciences Centre,
College School of Medicine,
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
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(Bell & Forsdyke, unpublished work; Dang et al. 1998, Biochem.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).