title: Increased global transcription activity as a mechanism of replication stress in cancer.
abstract: Cancer is a disease associated with genomic instability that often results from oncogene activation. This in turn leads to hyperproliferation and replication stress. However, the molecular mechanisms that underlie oncogene-induced replication stress are still poorly understood. Oncogenes such as HRASV12promote proliferation by upregulating general transcription factors to stimulate RNA synthesis. Here we investigate whether this increase in transcription underlies oncogene-induced replication stress. We show that in cells overexpressing HRASV12, elevated expression of the general transcription factor TATA-box binding protein (TBP) leads to increased RNA synthesis, which together with R-loop accumulation results in replication fork slowing and DNA damage. Furthermore, overexpression of TBP alone causes the hallmarks of oncogene-induced replication stress, including replication fork slowing, DNA damage and senescence. Consequently, we reveal that increased transcription can be a mechanism of oncogene-induced DNA damage, providing a molecular link between upregulation of the transcription machinery and genomic instability in cancer.
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Kotsantis
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
authors.forename: Lara Marques
authors.initials: LM
authors.lastname: Silva
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Irmscher
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Jones
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Folkes
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
authors.forename: Natalia
authors.initials: N
authors.lastname: Gromak
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Eva
authors.initials: E
authors.lastname: Petermann
mesh_terms: D045744:Cell Line, Tumor; D016922:Cellular Senescence; D004261:DNA Replication / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D009690:Nucleic Acid Conformation; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013312:Stress, Physiological; D035181:TATA-Box Binding Protein / Q000378:metabolism; D014158:Transcription, Genetic; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D012334:RNA, Neoplasm; D035181:TATA-Box Binding Protein; C509817:TBP protein, human; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)