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

Schneider, Maren, Hellerschmied, Doris, Schubert, Tobias, Amlacher, Stefan, Vinayachandran, Vinesh, Reja, Rohit, Pugh, B. Franklin, Clausen, Tim, Köhler, Alwin
Cell 2015 v.162 pp. 1016-1028
DNA-directed RNA polymerase, RNA transport, gene expression, genes, messenger RNA, nucleoporins, phenotype, phosphorylation, transcriptome
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.