A novel role for the Pol I transcription factor UBTF in maintaining genome stability through the regulation of highly transcribed Pol II genes
- Elaine Sanij1,7,
- Jeannine Diesch1,
- Analia Lesmana1,
- Gretchen Poortinga1,
- Grace Lidgerwood1,
- Nadine Hein1,
- Donald P Cameron1,
- Jason Ellul1,
- Gregory J Goodall2,
- Lee H Wong3,
- Amardeep S Dhillon1,
- Nourdine Hamdane4,
- Lawrence I Rothblum5,
- Richard B Pearson1,
- Izhak Haviv6,
- Thomas Moss4 and
- Ross D Hannan1
- 1 Peter MacCallum Cancer Centre;
- 2 The University of Adelaide;
- 3 Monash University;
- 4 Québec University Hospital Research Centre;
- 5 University of Oklahoma Health Sciences Center;
- 6 Bar-Ilan University
- ↵* Corresponding author; email: elaine.sanij{at}petermac.org
Abstract
Mechanisms to coordinate programs of highly transcribed genes required for cellular homeostasis and growth are unclear. Upstream binding transcription factor 1 (UBTF, also called UBF) is thought to function exclusively in RNA polymerase I (Pol I)-specific transcription of the ribosomal genes. Here we report that, the two isoforms of UBTF (UBTF1/2) are also enriched at highly expressed Pol II-transcribed genes throughout the mouse genome. Further analysis of UBTF1/2 DNA binding in immortalised human epithelial cells and their isogenically matched transformed counterparts reveals an additional repertoire of UBTF1/2-bound genes involved in the regulation of cell cycle checkpoints and DNA damage response. As proof of a functional role for UBTF1/2 in regulating Pol II transcription, we demonstrate that UBTF1/2 is required for recruiting Pol II to the highly transcribed histone gene clusters and for their optimal expression. Intriguingly, lack of UBTF1/2 does not affect chromatin marks or nucleosome density at histone genes. Instead it results in increased accessibility of the histone promoters and transcribed regions to micrococcal nuclease, implicating UBTF1/2 in mediating DNA accessibility. Unexpectedly, UBTF2, which does not function in Pol I transcription, is sufficient to regulate histone gene expression in the absence of UBTF1. Moreover, depletion of UBTF1/2 and subsequent reduction in histone gene expression is associated with DNA damage and genomic instability independent of Pol I transcription. Thus, we have uncovered a novel role for UBTF1 and UBTF2 in maintaining genome stability through coordinating the expression of highly transcribed Pol I (UBTF1 activity) and Pol II genes (UBTF2 activity).
- Received March 26, 2014.
- Accepted November 26, 2014.
- Published by Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International license), as described at http://creativecommons.org/licenses/by-nc/4.0/.
