During eukaryotic transcription elongation, RNA polymerase II (RNAP2) is regulated by a chorus of factors. Here, we identified a common binary interaction module consisting of TFIIS N-terminal domains (TNDs) and natively unstructured TND-interacting motifs (TIMs). This module was conserved among the elongation machinery and linked complexes including transcription factor TFIIS, Mediator, super elongation complex, elongin, IWS1, SPT6, PP1-PNUTS phosphatase, H3K36me3 readers, and other factors. Using nuclear magnetic resonance, live-cell microscopy, and mass spectrometry, we revealed the structural basis for these interactions and found that TND-TIM sequences were necessary and sufficient to induce strong and specific colocalization in the crowded nuclear environment. Disruption of a single TIM in IWS1 induced robust changes in gene expression and RNAP2 elongation dynamics, which underscores the functional importance of TND-TIM surfaces for transcription elongation.

Center for Cancer Epigenetics The University of Texas MD Anderson Cancer Center Houston TX USA

Center for Precision Environmental Health Department of Molecular and Cellular Biology and Dan L Duncan Comprehensive Cancer Center Baylor College of Medicine Houston TX USA

Department of Bioengineering Rice University Houston TX USA

Department of Biological Chemistry and Molecular Pharmacology Harvard Medical School Boston MA USA

Department of Cell Biology Faculty of Science Charles University Prague Czech Republic

Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Prague Czech Republic

Molecular Virology and Gene Therapy KU Leuven Leuven Flanders Belgium

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