title: A novel role for the Pol I transcription factor UBTF in maintaining genome stability through the regulation of highly transcribed Pol II genes.
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).
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia; Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia; elaine.sanij@petermac.org ross.hannan@petermac.org.
authors.forename: Elaine
authors.initials: E
authors.lastname: Sanij
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Jeannine
authors.initials: J
authors.lastname: Diesch
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Analia
authors.initials: A
authors.lastname: Lesmana
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia; Department of Medicine, University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Gretchen
authors.initials: G
authors.lastname: Poortinga
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Nadine
authors.initials: N
authors.lastname: Hein
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia;
authors.forename: Grace
authors.initials: G
authors.lastname: Lidgerwood
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Donald P
authors.initials: DP
authors.lastname: Cameron
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Jason
authors.initials: J
authors.lastname: Ellul
authors.affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia 5000, Australia; Discipline of Medicine, The University of Adelaide, Adelaide, South Australia 5005, Australia; School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia 5005, Australia;
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Goodall
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia;
authors.forename: Lee H
authors.initials: LH
authors.lastname: Wong
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia; Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Amardeep S
authors.initials: AS
authors.lastname: Dhillon
authors.affiliation: Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Laval University, Québec, QC, G1V 0A6, Canada; St-Patrick Research Group in Basic Oncology, Québec University Hospital Research Centre, Québec, QC, G1R 3S3, Canada;
authors.forename: Nourdine
authors.initials: N
authors.lastname: Hamdane
authors.affiliation: Department of Cell Biology, University of Oklahoma College of Medicine, Oklahoma City, Oklahoma 73104, USA;
authors.forename: Lawrence I
authors.initials: LI
authors.lastname: Rothblum
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Richard B
authors.initials: RB
authors.lastname: Pearson
authors.affiliation: Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia; Faculty of Medicine, Bar-Ilan University, Zfat, 13100, Israel;
authors.forename: Izhak
authors.initials: I
authors.lastname: Haviv
authors.affiliation: Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Laval University, Québec, QC, G1V 0A6, Canada; St-Patrick Research Group in Basic Oncology, Québec University Hospital Research Centre, Québec, QC, G1R 3S3, Canada;
authors.forename: Tom
authors.initials: T
authors.lastname: Moss
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3010, Australia; Division of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; School of Biomedical Sciences, University of Queensland, Brisbane 4072, Queensland, Australia elaine.sanij@petermac.org ross.hannan@petermac.org.
authors.forename: Ross D
authors.initials: RD
authors.lastname: Hannan
mesh_terms: D000818:Animals; D001665:Binding Sites; D002461:Cell Line, Transformed; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology; D004249:DNA Damage; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D042822:Genomic Instability; D059014:High-Throughput Nucleotide Sequencing; D006657:Histones / Q000235:genetics; D006801:Humans; D051379:Mice; D005810:Multigene Family; D041681:NIH 3T3 Cells; D009707:Nucleosomes / Q000378:metabolism; D035463:Pol1 Transcription Initiation Complex Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D012318:RNA Polymerase I / Q000235:genetics*; D012319:RNA Polymerase II / Q000235:genetics*; D024363:Transcription Initiation Site; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D006657:Histones; D009707:Nucleosomes; D035463:Pol1 Transcription Initiation Complex Proteins; C063844:transcription factor UBF; D012319:RNA Polymerase II; D012318:RNA Polymerase I