A novel role for the Pol I transcription factor TBTF in maintaining genome stability through the regulation of highly transcribed Pol II genes

Sanij, Elaine, Diesch, Jeannine, Lesmana, Analia, Poortinga, Gretchen, Hein, Nadine, Lidgerwood, Grace, Cameron, Donald P., Ellul, Jason, Goodall, Gregory J., Wong, Lee H., Dhillon, Amardeep S., Hamdane, Nourdine, Rothblum, Lawrence I., Pearson, Richard B., Haviv, Izhak, Moss, Tom and Hannan, Ross D. (2015) A novel role for the Pol I transcription factor TBTF in maintaining genome stability through the regulation of highly transcribed Pol II genes. Genome Research, 25 2: 201-212. doi:10.1101/gr.176115.114


Author Sanij, Elaine
Diesch, Jeannine
Lesmana, Analia
Poortinga, Gretchen
Hein, Nadine
Lidgerwood, Grace
Cameron, Donald P.
Ellul, Jason
Goodall, Gregory J.
Wong, Lee H.
Dhillon, Amardeep S.
Hamdane, Nourdine
Rothblum, Lawrence I.
Pearson, Richard B.
Haviv, Izhak
Moss, Tom
Hannan, Ross D.
Title A novel role for the Pol I transcription factor TBTF in maintaining genome stability through the regulation of highly transcribed Pol II genes
Journal name Genome Research   Check publisher's open access policy
ISSN 1549-5469
1088-9051
Publication date 2015-02-01
Year available 2014
Sub-type Article (original research)
DOI 10.1101/gr.176115.114
Open Access Status DOI
Volume 25
Issue 2
Start page 201
End page 212
Total pages 12
Place of publication Cold Spring Harbor, NY United States
Publisher Cold Spring Harbor Laboratory Press
Collection year 2015
Language eng
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).
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online ahead of print 1 Dec 2014

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Biomedical Sciences Publications
 
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