Increased global transcription activity as a mechanism of replication stress in cancer
Research output: Contribution to journal › Article › peer-review
Colleges, School and Institutes
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.
|Number of pages||13|
|Early online date||11 Oct 2016|
|Publication status||Published - Dec 2016|
- RAS, oncogenes, TBP, R-loops, RNA/DNA hybrids, replication stress, DNA damage, genome instability