Critical interactions of neuronal transcription factor REST with stabilizer TRF2

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BROM Tomáš JANOVIČ Tomáš VEVERKA Pavel STOJASPAL Martin HOFR Ctirad

Rok publikování 2022
Druh Konferenční abstrakty
Fakulta / Pracoviště MU

Přírodovědecká fakulta

Citace
Popis Glioblastoma is the most common and malignant brain tumor in adults. Glioblastoma is highly resistant to chemotherapy and radiotherapy. So far, there has been no successful treatment. Recent studies revealed a strong correlation between glioblastoma tumorigenicity and the aberrant expression of REST, the main repressor of neural stem cell differentiation [1].

The fate of the REST inside cells is mainly regulated by ubiquitylation. The primary protecting role is played by telomeric factor TRF2 that forms a complex with REST and protects it from ubiquitylation and therefore from proteasomal degradation [2]. TRF2 also forms the core of the shelterin complex that shields chromosome ends against unwanted end-joining and DNA repair machinery. REST indirectly regulates TRF2 expression; thus, it affects shelterin complex formation [3]. REST TRF2 complex disruption is a promising target of molecular therapy that will provide a dual effect on cancer stem cells.

Here, we have investigated in cell localization of REST and TRF2, and we have observed the formation of REST-TRF2 complex directly in the cell nucleus using Proximity ligation assay. We have determined the structure of transcription factor REST using cryo-electron microscopy single-particle reconstruction. A better understanding of the REST-TRF2 complex will provide valuable knowledge in development of drugs against glioblastoma.

1. D. Zhang, Y. Li, R. Wang, Y. Li, P. Shi, Z. Kan, X. Pang, Int. J. Mol. Sci., 17, (2016), 664. 2. Z. Huang, and S. Bao, FEBS letters, 586, (2012), 1602. 3. P. Ovando-Roche, J.S.L. Yu, S. Testori, C. Ho, W. Cui, Stem Cells, 32, (2014), 2111.

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