Critical interactions of neuronal transcription factor REST with stabilizer TRF2

T. Brom, T. Janovič, P. Veverka, M. Stojaspal, C. Hofr

LifeB, National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Brno, Czech Republic

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.

This work is supported by Brno Ph.D. Talent Scholarship - funded by Brno City Municipality. The Czech Science Foundation [19-18226S] has primarily supported this research. The research has been carried out with institutional support of the Ministry of Education, Youth and Sports of the Czech Republic under the projects LTAUSA19024. We acknowledge the core facility CELLIM supported by MEYS CR (LM2018129 Czech-BioImaging) and Cryo-electron microscopy and tomography core facility CEITEC MU of CIISB, Instruct-CZ Centre supported by MEYS CR (LM2018127).