Abstract
Cancer is a disease associated with genomic instability that often results from oncogene activation. This in turn, leads to hyper-proliferation and replication stress. However, the molecular mechanisms that underlie oncogene-induced replication stress are still poorly understood. Oncogenes such as HRASV12 promote proliferation by up-regulating 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 major mechanism of oncogene-induced DNA damage, providing a molecular link between up-regulation of the transcription machinery and genomic instability in cancer.
Original language | English |
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Article number | 13087 |
Number of pages | 13 |
Journal | Nature Communications |
Volume | 7 |
DOIs | |
Publication status | Published - 11 Oct 2016 |
Data Access Statement
The authors declare that all the data supporting the findings ofthis study are available within the article and its Supplementary Information files
and from the corresponding authors upon reasonable request.