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(Bell & Forsdyke, unpublished work; Dang et al. 1998, Biochem.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). |
