Increased global transcription activity as a mechanism of replication stress in cancer

Panagiotis Kotsantis, Lara Marques Silva, Sarah Irmscher, Rebecca M. Jones, Lisa Folkes, Natalia Gromak () and Eva Petermann ()
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Panagiotis Kotsantis: Institute of Cancer and Genomic Sciences, University of Birmingham
Lara Marques Silva: Sir William Dunn School of Pathology, University of Oxford
Sarah Irmscher: Sir William Dunn School of Pathology, University of Oxford
Rebecca M. Jones: Institute of Cancer and Genomic Sciences, University of Birmingham
Lisa Folkes: CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford
Natalia Gromak: Sir William Dunn School of Pathology, University of Oxford
Eva Petermann: Institute of Cancer and Genomic Sciences, University of Birmingham

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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 HRASV12 promote 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.

Date: 2016
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DOI: 10.1038/ncomms13087

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