Abstract

Post-transcriptional gene silencing is a critical step towards maintenance of a cell’s unique gene expression profile. While degradation of mRNA ensures that the level of a transcript, and eventually, its protein product is down regulated, translational repression rapidly blocks protein production without perturbing mRNA levels. Not surprisingly, translational repression has been found to precede mRNA decay in many pathways of cellular mRNA turnover. Of the known pathways of mRNA turnover, ARE-mediated decay (AMD) is especially important as many highly labile mRNAs (those of cytokines, interferons and transcription factors) contain AREs in their 3'-untranslated regions (3'-UTR) and are degraded by AMD. Consistently, AMD and the proteins involved therein are implicated in several inflammatory and autoimmune disorders and form an important platform for therapeutic intervention.

A well-studied example of a protein involved in AMD is TTP. TTP specifically binds ARE-sequences and recruits the mRNA degradation machinery. More recently, TTP was also shown to mediate translational repression of its target transcript. Although the recruitment of the mRNA degradation and the translational repression machinery to the target mRNA by TTP is well understood, it is not known how or if the events of decay and translational repression are linked to each other. Furthermore, it is still unclear whether assembly of the repression machinery on the mRNA influences assembly of the decay machinery and vice-versa.

We propose to analyse the interplay and interdependence of the mRNA decay and translational repression processes using a combination of structural, biochemical and cell-based methods. These experiments will provide mechanistic insight into the dynamic assembly and remodelling of mRNPs involved in mRNA decay and translational repression and lead us to appreciate how these processes are physically and functionally coupled in cells.

Project-related publications

Gowravaram, M., Schwarz, J., Khilji, S.K., Urlaub, H., Chakrabarti, S. (2019) Insights into the assembly and architecture of a Staufen mediated mRNA decay (SMD)-competent mRNP. Nat. Commun. 10, 5054, doi:10.1038/s41467-019-13080-x

Gowravaram, M., Bonneau, F., Kanaan, J., Maciej, V.D., Fiorini, F., Raj, S., Croquette, V., Le Hir, H., Chakrabarti, S. (2018) A conserved structural element in the RNA helicase UPF1 regulates its catalytic activity in an isoform-specific manner. Nucleic Acids Res, 46(5): 2648-2659