A novel role for the Pol I transcription factor UBTF in maintaining genome stability through the regulation of highly transcribed Pol II genes
- Elaine Sanij1,2,3,
- Jeannine Diesch1,2,
- Analia Lesmana1,2,
- Gretchen Poortinga1,2,4,
- Nadine Hein1,2,
- Grace Lidgerwood1,
- Donald P. Cameron1,2,
- Jason Ellul1,2,
- Gregory J. Goodall5,6,7,
- Lee H. Wong8,
- Amardeep S. Dhillon1,2,3,
- Nourdine Hamdane9,10,
- Lawrence I. Rothblum11,
- Richard B. Pearson1,2,8,12,
- Izhak Haviv3,13,16,
- Tom Moss9,10 and
- Ross D. Hannan1,2,8,12,14,15,16
- 1Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia;
- 2Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia;
- 3Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia;
- 4Department of Medicine, University of Melbourne, Parkville, Victoria 3010, Australia;
- 5Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia 5000, Australia;
- 6Discipline of Medicine, The University of Adelaide, Adelaide, South Australia 5005, Australia;
- 7School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia 5005, Australia;
- 8Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia;
- 9Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Laval University, Québec, QC, G1V 0A6, Canada;
- 10St-Patrick Research Group in Basic Oncology, Québec University Hospital Research Centre, Québec, QC, G1R 3S3, Canada;
- 11Department of Cell Biology, University of Oklahoma College of Medicine, Oklahoma City, Oklahoma 73104, USA;
- 12Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3010, Australia;
- 13Faculty of Medicine, Bar-Ilan University, Zfat, 13100, Israel;
- 14Division of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia;
- 15School of Biomedical Sciences, University of Queensland, Brisbane 4072, Queensland, Australia
- Corresponding authors: elaine.sanij{at}petermac.org, ross.hannan{at}petermac.org
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↵16 These authors contributed equally to this work.
Abstract
Mechanisms to coordinate programs of highly transcribed genes required for cellular homeostasis and growth are unclear. Upstream binding transcription factor (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 immortalized 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).
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.176115.114.
Freely available online through the Genome Research Open Access option.
- Received March 26, 2014.
- Accepted November 26, 2014.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
