Pol II phosphorylation regulates a switch between transcriptional and splicing condensates
Author(s)Manteiga, John Colonnese; Spille, Jan Hendrik; Afeyan, Lena K.; Zamudio Montes de Oca, Alicia; Shrinivas, Krishna; Cisse, Ibrahim I; Sharp, Phillip A.; Young, Richard A.; ... Show more Show less
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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 complex1–4. 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 apparatus5,6. Recent observations suggest that this model provides only a partial picture of the effects of phosphorylation of the C-terminal domain7–12. 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-enhancers7,8, and large numbers of splicing factors are concentrated in nuclear speckles, some of which occur at highly active transcription sites9–12. 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.
DepartmentMassachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Department of Physics; Massachusetts Institute of Technology. Department of Chemical Engineering; Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Springer Science and Business Media LLC
Yang Eric Guo et al. "Pol II phosphorylation regulates a switch between transcriptional and splicing condensates." Nature 572(2019): 543-548 © 2018 The Author(s)
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