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Nucleic Acids Research, 1995, Vol. 23, No. 1 138-145
© 1995

MOLECULAR BIOLOGY

A transcriptional repressor obtained by alternative translation of a trinucleotide repeat

Rainer B. Lanz1, Stefan Wieland1,2, Martin Hug1 and Sandro Rusconi1,3,*

1Institut für Molekularbiologie II der Universität Zurich UZI Winterthurerstrasse 190, 8057 Zurich, Switzerland 2Medizinische Universitatsklinik Universitatsklinik, Hugstetterstrasse 55, D-79106 Freiburg, Germany 3Biochemisches Institut, Universität Fribourg Pérolles, CH-1700 Fribourg, Switzerland

*To whom correspondence should be addressed at: Biochemisches Institut, Universität Fribourg, Pérolles. CH-1700 Fribourg, Switzerland

Received September 19, 1994. Revised November 23, 1994. Accepted November 23, 1994.

Triplet nucleotide repeats are ubiquitous and rapidly evolving sequences in eucaryotic genomes. They are sporadically found in coding regions of transcription regulators where they become translated in different homopolymeric aminoacid (HPAA) stretches, depending on the local frame. Poly(CAG) yields three different HPAAs (poly Gln, Ser or Ala). Current sequence databases indicate a clear bias in the size and frequency of these HPAAs according to the rule: (Gln)n>(Ser)n>>(Ala)n. Aiming to understand the reasons of this bias, we changed the translational reading frame of the highly polymorphic CAG-repeat that normally encodes poly-Gln in the N-terminal portion of the rat glucocorticoid receptor (GR). The GR mutant in which the CAG repeat is translated to poly-Ala (called GR[Ala]) is incapable of transactivation, but maintains competence for hormone binding, nuclear translocation and specific DNA binding. We show that GR desactivation is obtained only when a very precise threshold length of the repeat is reached. GR[Ala] displays a strong negative dominance when tested for transcriptional activation in vivo and may become useful for selective competition of receptor dependent activities in tissue culture cells and transgenic animals. We discuss the implications of our findings for the understanding of the evolutionary behaviour of trinucleotide repeats in coding sequences.


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