Pol II phosphorylation regulates a switch between transcriptional and splicing condensates.

Autor: Guo YE; Whitehead Institute for Biomedical Research, Cambridge, MA, USA., Manteiga JC; Whitehead Institute for Biomedical Research, Cambridge, MA, USA.; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA., Henninger JE; Whitehead Institute for Biomedical Research, Cambridge, MA, USA., Sabari BR; Whitehead Institute for Biomedical Research, Cambridge, MA, USA., Dall'Agnese A; Whitehead Institute for Biomedical Research, Cambridge, MA, USA., Hannett NM; Whitehead Institute for Biomedical Research, Cambridge, MA, USA., Spille JH; Department of Physics, Massachusetts Institute of Technology, Cambridge, MA, USA.; Department of Physics, University of Illinois at Chicago, Chicago, IL, USA., Afeyan LK; Whitehead Institute for Biomedical Research, Cambridge, MA, USA.; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA., Zamudio AV; Whitehead Institute for Biomedical Research, Cambridge, MA, USA.; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA., Shrinivas K; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.; Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA., Abraham BJ; Whitehead Institute for Biomedical Research, Cambridge, MA, USA.; Computational Biology, St Jude Children's Research Hospital, Memphis, TN, USA., Boija A; Whitehead Institute for Biomedical Research, Cambridge, MA, USA., Decker TM; Department of Biochemistry, University of Colorado, Boulder, CO, USA., Rimel JK; Department of Biochemistry, University of Colorado, Boulder, CO, USA., Fant CB; Department of Biochemistry, University of Colorado, Boulder, CO, USA., Lee TI; Whitehead Institute for Biomedical Research, Cambridge, MA, USA., Cisse II; Department of Physics, Massachusetts Institute of Technology, Cambridge, MA, USA., Sharp PA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA., Taatjes DJ; Department of Biochemistry, University of Colorado, Boulder, CO, USA., Young RA; Whitehead Institute for Biomedical Research, Cambridge, MA, USA. young@wi.mit.edu.; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. young@wi.mit.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2019 Aug; Vol. 572 (7770), pp. 543-548. Date of Electronic Publication: 2019 Aug 07.
DOI: 10.1038/s41586-019-1464-0
Abstrakt: The synthesis of pre-mRNA by RNA polymerase II (Pol II) involves the formation of a transcription initiation complex, and a transition to an elongation complex 1-4 . The large subunit of Pol II contains an intrinsically disordered C-terminal domain that is phosphorylated by cyclin-dependent kinases during the transition from initiation to elongation, thus influencing the interaction of the C-terminal domain with different components of the initiation or the RNA-splicing apparatus 5,6 . Recent observations suggest that this model provides only a partial picture of the effects of phosphorylation of the C-terminal domain 7-12 . Both the transcription-initiation machinery and the splicing machinery can form phase-separated condensates that contain large numbers of component molecules: hundreds of molecules of Pol II and mediator are concentrated in condensates at super-enhancers 7,8 , and large numbers of splicing factors are concentrated in nuclear speckles, some of which occur at highly active transcription sites 9-12 . Here we investigate whether the phosphorylation of the Pol II C-terminal domain regulates the incorporation of Pol II into phase-separated condensates that are associated with transcription initiation and splicing. We find that the hypophosphorylated C-terminal domain of Pol II is incorporated into mediator condensates and that phosphorylation by regulatory cyclin-dependent kinases reduces this incorporation. We also find that the hyperphosphorylated C-terminal domain is preferentially incorporated into condensates that are formed by splicing factors. These results suggest that phosphorylation of the Pol II C-terminal domain drives an exchange from condensates that are involved in transcription initiation to those that are involved in RNA processing, and implicates phosphorylation as a mechanism that regulates condensate preference.
Databáze: MEDLINE
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