Summary
RNA Polymerase II (Pol II) plays a pivotal role in human cellular function, carrying out the complex transcription process. A unique domain sits at the end of Pol II, the C-Terminal Domain (CTD), the phosphorylation of which offers a mechanism of interaction for transcription factors (TFs) that regulate the transcription process. The spatial organization of TFs around Pol II is moderated by the intrinsically disordered regions (IDRs) of the TFs and CTD, and high specificity is required to avoid disease causing defects. However, the exact mechanisms that maintain this environment, and their importance are still unknown. Here we suggest a method for determining crucial Pol II – TF interactions by relating electromagnetic imaging to computer simulations. Results will be able to delineate individual amino acids responsible for maintaining the spatial organization of the proteins in vitro. The simulation-based study will be leveraged to explore the tolerance of maintaining these interactions when encountered with different phosphorylation states of CTD. A proof-of-concept study is then described which will demonstrate an ability to actively target IDRs to stabilize the protein interactions. While the results here will be comprehensive for four TFs of interest (RECQL5, SCAF4, SCAF8, and the SOSS1 complex), the methodology can then be expanded to characterize a library of over 400 TFs. Such a project has the potential to not only further our understanding of CTDs function, but also pave a way for designing synthetic treatments that can regulate the transcription process.
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| Web resources: | https://cordis.europa.eu/project/id/101180586 |
| Start date: | 01-05-2024 |
| End date: | 30-04-2026 |
| Total budget - Public funding: | - 150 438,00 Euro |
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Original description
RNA Polymerase II (Pol II) plays a pivotal role in human cellular function, carrying out the complex transcription process. A unique domain sits at the end of Pol II, the C-Terminal Domain (CTD), the phosphorylation of which offers a mechanism of interaction for transcription factors (TFs) that regulate the transcription process. The spatial organization of TFs around Pol II is moderated by the intrinsically disordered regions (IDRs) of the TFs and CTD, and high specificity is required to avoid disease causing defects. However, the exact mechanisms that maintain this environment, and their importance are still unknown. Here we suggest a method for determining crucial Pol II – TF interactions by relating electromagnetic imaging to computer simulations. Results will be able to delineate individual amino acids responsible for maintaining the spatial organization of the proteins in vitro. The simulation-based study will be leveraged to explore the tolerance of maintaining these interactions when encountered with different phosphorylation states of CTD. A proof-of-concept study is then described which will demonstrate an ability to actively target IDRs to stabilize the protein interactions. While the results here will be comprehensive for four TFs of interest (RECQL5, SCAF4, SCAF8, and the SOSS1 complex), the methodology can then be expanded to characterize a library of over 400 TFs. Such a project has the potential to not only further our understanding of CTDs function, but also pave a way for designing synthetic treatments that can regulate the transcription process.Status
SIGNEDCall topic
HORIZON-WIDERA-2023-TALENTS-02-01Update Date
23-11-2024
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