The Nuclear Pore-Associated TREX-2 Complex Employs Mediator to Regulate Gene Expression

Nuclear pore complexes (NPCs) influence gene expression besides their established function in nuclear transport. The TREX-2 complex localizes to the NPC basket and affects gene-NPC interactions, transcription, and mRNA export. How TREX-2 regulates the gene expression machinery is unknown. Here, we show that TREX-2 interacts with the Mediator complex, an essential regulator of RNA Polymerase (Pol) II. Structural and biochemical studies identify a conserved region on TREX-2, which directly binds the Mediator Med31/Med7N submodule. TREX-2 regulates assembly of Mediator with the Cdk8 kinase and is required for recruitment and site-specific phosphorylation of Pol II. Transcriptome and phenotypic profiling confirm that TREX-2 and Med31 are functionally interdependent at specific genes. TREX-2 additionally uses its Mediator-interacting surface to regulate mRNA export suggesting a mechanism for coupling transcription initiation and early steps of mRNA processing. Our data provide mechanistic insight into how an NPC-associated adaptor complex accesses the core transcription machinery. [Display omitted] •The nuclear pore-associated TREX-2 complex directly interacts with Mediator•TREX-2 regulates Mediator association with Cdk8 and RNA Pol II Ser5 phosphorylation•TREX-2 and the Med31 submodule co-regulate specific inducible and constitutive genes•A similar TREX-2 surface promotes both transcription and mRNA export The NPC-associated TREX-2 complex directly interacts with Mediator, which in turn scaffolds RNA Pol II transcription initiation thus revealing how an NPC-associated adaptor complex accesses the core transcription machinery.