Medizinische Klinik A

Translationale Regulation der Genexpression

Focus

Our group is interested in the patho-physiological implications of upstream open reading frame (uORF)-mediated translational regulation of gene expression.

Model of a uORF-containing transcript

Two uORFs (blue boxes) precede the main ORF of the coding sequence (white box). Ribosomes may initiate at the coding sequence initiation codon (white flag) after leaky scanning through both uORF initiation codons (blue flags), or may reinitiate after translating the first uORF and leaky scanning through the second uORF initiation site. Ribosomes translating the second overlapping uORF will not be available for translation of the coding sequence.

Upstream ORFs are defined by translational initiation codons preceding the main protein coding sequence (CDS) followed by an in-frame termination codon (uStop). Approximately 55% of human transcript leader sequences (TLSs) contain one or multiple AUG-initiated uORFs, which may precede or overlap with the CDS initiation site. During canonical cap-dependent translation ribosomes frequently initiate at upstream AUG (uAUG) codons, resulting in reduced translation of the associated downstream CDS. Upstream ORFs throttle translation rates at the CDS by various mechanisms, including consumption of ribosomal pre-initiation complexes, induction of ribosome stalling at uStop codons, and nonsense-mediated mRNA decay. Defective uORF-mediated translational control alters physiological processes across species from yeast to mice and has been implicated in the onset of several inherited diseases, including cancer. 

Mechanistic modes of uORF-mediated translational control

A) Simplified model of uORF-mediated expression regulation of yeast GCN4 in response to stress-induced depletion of the eIF2–GTP–Met-tRNAi complex. See main text for a detailed description. The figure uses the same graphical layout as introduced in figure 1.
B to E) Graphic representations of ligand-induced ribosome stalling at peptide-specific uORFs, of nonsense-mediated decay induced by ribosome stalling at uORF termination codons, of uORF-directed start site selection of post-termination ribosomes, and of uORF-dependent ribosome shunting across inhibitory secondary structures within the TLS.

 
 
 
 

Kontakt

Universitätsklinikum Münster Medizinische Klinik A
AG Translationale Regulation der Genexpression

Leitung
Dr.med. Dr.rer.nat. Klaus Wethmar

Albert-Schweitzer-Campus 1, Gebäude D3,

Anfahtsadresse: Domagkstr. 3 | 48149 Münster

Tel.: 0049-(0)251/83-52721
Fax: 0049-0(251)-83-52673

E-Mail: