1. TISU, a prevalent regulatory element that controls both transcription and translation
Transcription is controlled by regulatory elements, proximal and distal relative to the transcription start site (TSS). Some proximal elements are localized downstream to the TSS, and are present in the mRNA as well, where they could also influence translation.
In a search for promoter regulatory elements in the poorly characterized class of TATA-less genes, we identified a prevalent transcription regulatory motif in a defined downstream location. Remarkably this motif also serves as a Translation Initiator of Short 5’UTR (TISU) mRNAs. This composite element functions in a sizeable fraction of genes (~1300 genes) and is most likely an essential regulatory element as it is present in genes with vital cellular functions that are characterized by an unusually short 5’UTR. Elucidating the mechanism and the regulatory role of TISU is therefore of paramount importance.
We showed that TISU directs a unique mode of translation initiation that is cap-dependent but scanning-free. Evidence from our most recent research suggests that a key step in recognition of an AUG located close to the 5’end of mRNAs involves eviction of the cap complex. We also showed that the translation initiation factors eIF4GI and eIF1 cooperate to facilitate TISU function.
Elucidating the physiological significance of this mechanism revealed that TISU confers tolerance to global inhibition of translation under energy stress and in response to anti-diabetic drugs.
2. The impact of transcription start site selection on translation
The transcription start site is a critical determinant of 5’UTR length and content. The 5'UTR plays an important regulatory role in translation initiation. In mammalian cells many genes are characterized by multiple transcription start sites (TSSs), some are strictly clustered while others are spaced apart. Thus many genes display transcript variants that differ in their 5’UTR length and sequence. Using combination of TSS mapping with measurements of translation efficiency we are analyzing the contribution of the TSS to translational control.