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The TRF2 General Transcription Factor Is a Key Regulator of Cell Cycle Progression

Adi Kedmi, +11 more
- 03 May 2020 - 
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TLDR
It is demonstrated that TRF2 knockdown regulates cell cycle progression and exerts distinct effects on G1 and specific mitotic phases, uncovering a critical and unanticipated role of a general transcription factor as a key regulator of cell cycle.
Abstract: 
TRF2 (TATA-box-binding protein-related factor 2) is an evolutionarily conserved general transcription factor that is essential for embryonic development of Drosophila melanogaster, C. elegans, zebrafish and Xenopus. Nevertheless, the cellular processes that are regulated by TRF2 are largely underexplored. Here, using Drosophila Schneider cells as a model, we discovered that TRF2 regulates cell cycle progression. Using flow cytometry, high-throughput microscopy and advanced imaging-flow cytometry, we demonstrate that TRF2 knockdown regulates cell cycle progression and exerts distinct effects on G1 and specific mitotic phases. RNA-seq analysis revealed that TRF2 regulates the expression of Cyclin E and the mitotic cyclins, Cyclin A, Cyclin B and Cyclin B3, but not Cyclin D or Cyclin C. To identify proteins that could account for the observed regulation of these cyclin genes, we searched for TRF2-interacting proteins. Interestingly, mass spectrometry analysis of TRF2-containing complexes identified GFZF, a nuclear glutathione S-transferase implicated in cell cycle regulation, and Motif 1 binding protein (M1BP). Furthermore, available ChIP-exo data revealed that TRF2, GFZF and M1BP co-occupy the promoters of TRF2-regulated genes. Using RNAi to knockdown the expression of either M1BP, GFZF, TRF2 or their combinations, we demonstrate that although GFZF and M1BP interact with TRF2, it is TRF2, rather than GFZF or M1BP, that is the main factor regulating the expression of Cyclin E and the mitotic cyclins. Taken together, our findings uncover a critical and unanticipated role of a general transcription factor as a key regulator of cell cycle.

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(which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprintthis version posted May 3, 2020. ; https://doi.org/10.1101/2020.03.27.011288doi: bioRxiv preprint
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(which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
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(which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprintthis version posted May 3, 2020. ; https://doi.org/10.1101/2020.03.27.011288doi: bioRxiv preprint
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(which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprintthis version posted May 3, 2020. ; https://doi.org/10.1101/2020.03.27.011288doi: bioRxiv preprint
Citations
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TL;DR: A review of the TBP family and their interactions with the TATA-box on DNA can be found in this paper , where three TBP related factors (TRFs) or TBP-like factors (TBPLs) have been discovered in metazoans, TRF1, TBPL1, and TBPL2.
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