TY - JOUR
T1 - The Nuclear Pore-Associated TREX-2 Complex Employs Mediator to Regulate Gene Expression
AU - Schneider, Maren
AU - Hellerschmied, Doris
AU - Schubert, Tobias
AU - Amlacher, Stefan
AU - Vinayachandran, Vinesh
AU - Reja, Rohit
AU - Pugh, B. Franklin
AU - Clausen, Tim
AU - Köhler, Alwin
N1 - Funding Information:
We thank J. Cibulka and K. Lipp for assistance, the CSF NGS unit for RNA-seq, and S. Juntilla (CSF Biocomp) for bioinformatic analyses. We acknowledge R. Young, Y. Takagi, C. Dargemont, and D. Bentley for antibodies, S. Tan for the pST44 vector and G. Warren and J. Brennecke for comments on the manuscript. A. Köhler is funded by an ERC grant (281354; NPC GENEXPRESS) and a START grant from the Austrian Science Fund (FWF; Y557-B11). The IMP is funded by Boehringer Ingelheim. B.F.P. is funded by NIH grant GM059055 and has a financial interest in Peconic, LLC, which utilizes ChIP-exo and could potentially benefit from the outcomes of this research.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/8/27
Y1 - 2015/8/27
N2 - Summary 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.
AB - Summary 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.
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U2 - 10.1016/j.cell.2015.07.059
DO - 10.1016/j.cell.2015.07.059
M3 - Article
C2 - 26317468
AN - SCOPUS:84940504501
SN - 0092-8674
VL - 162
SP - 1016
EP - 1028
JO - Cell
JF - Cell
IS - 5
ER -