When TRF2 is around, REST is in peace - Structural and functional implications of extratelomeric TRF2 protecting neuronal differentiation regulator REST in glioblastoma
| Název česky | Když je TRF2 nablízku, REST je v klidu - Strukturální a funkční důsledky extratelomerického TRF2 chránícího regulátor neuronální diferenciace REST u glioblastomu |
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| Autoři | |
| Rok publikování | 2022 |
| Druh | Konferenční abstrakty |
| Citace | |
| Popis | Telomeric repeat binding factor TRF2, during extratelomeric activities, binds REST – RE1 - silencing transcription factor essential for keeping neuronal cells undifferentiated. TRF2 protects REST from ubiquitination and subsequent proteasomal degradation. REST activity is critical for the development and growth of glioblastoma – the most common and aggressive brain tumor in adults. The current effective treatment of glioblastoma is limited to rigorous surgical resection. The primary motivation for the research of TRF2-REST complex is finding a molecular way to slow down glioblastoma progression on a molecular level. We combined cell immunolocalization studies, molecular biology approaches, biophysical methods, and structural analyses – (i) to reveal the proximity of TRF2-REST in vivo, (ii) to describe binding affinities, and (iii) to characterize the structure of the complex in vitro. We carried out proximity ligation analyses in differentiated and undifferentiated neuronal cells showing that REST and TRF2 are assembled in both cell types. Additionally, we quantified the mutual binding of TRF2 and REST. Further, cryo-electron microscopy studies of full-length REST revealed a surprising donut-like shape. Finally, we characterized interacting regions of REST and TRF2 using hydrogen-deuterium exchange mass spectrometry by measuring the proton exchange rate on individual amino acids. Implications of our findings for the molecular intervention of glioblastoma development will be discussed. Acknowledgments: Czech Science Foundation (19-18226S); Ministry of Education, Youth and Sports of the Czech Republic (LTAUSA19024); Institute of Biophysics of the Czech Academy of Sciences (68081707), and Brno Ph.D. Talent Scholarship to T.B. funded by Brno City Municipality. |
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