Events and seminars

The nuclear cap-binding complex (CBC), which consists of CBP20 and CBP80, has been implicated in numerous aspects of gene expression in the nucleus¹ and in the cytoplasm². 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 elongation³. 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)⁴, 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 mRNAs⁵. Our unpublished results indicate that NCBP3 competes with splicing and decay factors for the binding to ARS2, thereby generating a chromatin-associated reservoir of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.