Nuclear cap-binding proteins, pre-mRNA quality control, and gene activation


15th May - 12:30
Léon Fredericq Auditorium
GIGA B34 +5

The nuclear cap-binding complex (CBC), which consists of CBP20 and CBP80, has been implicated in numerous aspects of gene expression in the nucleus and in the cytoplasm. We report that the CBC and its accessory proteins target different steps of pre-mRNA metabolism to induce distinct sets of genes.

In a first quality and quantity control mechanism, the transcriptional co-activator PGC-1α senses CBP80 at the cap of nascent pre-mRNAs deriving from stress-activated genes during promoter-proximal pausing of RNAPII to allow for transcription elongation. Using mouse C2C12 myoblasts as a model, we found that the direct binding of the C-terminal region of PGC-1α to CBP80 and the MED1 subunit of Mediator (i) prevents the recruitment of the premature transcription termination complex Integrator, and (ii) facilitates the recruitment of the positive transcription elongation factor b (P-TEFb). We used an in-house mouse model to show that this mechanism ensures efficient differentiation of primary myoblasts to myofibers and timely skeletal-muscle regeneration after injury.

A second independent mechanism involves the poorly characterized nuclear cap-binding protein 3 (NCBP3), which binds the CBC via ARS2 after release of RNAPII from pausing. CBC-bound ARS2 acts as a sorting platform for nascent pre-mRNAs and newly synthesized mRNAs. Our unpublished results indicate that NCBP3 competes with splicing and decay factors for the binding to ARS2, thereby generating a chromatin-associated reservoir of intron-containing poly(A)+ pre-mRNAs. Many NCBP3-stabilized poly(A)+ pre-mRNAs, which structurally differ from detained-intron pre-mRNAs, derive from PGC-1α-activated genes that promote mitochondrial biology. We show that these pre-mRNAs slowly accumulate and then are slowly post-transcriptionally spliced during the multi-day differentiation of myoblasts into myotubes, likely contributing to the cellular adaptation to changing respiration needs.

Contact at GIGA : Yvette Habraken

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