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

Kotsantis, P. and Silva, L.M. and Irmscher, S. and Jones, R.M. and Folkes, L. and Gromak, N. and Petermann, E. (2016) Increased global transcription activity as a mechanism of replication stress in cancer. Nature Communications, 7: 13087. ISSN 2041-1723

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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.

Item Type:
Journal Article
Journal or Publication Title:
Nature Communications
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/1300/1300
Subjects:
?? general biochemistry,genetics and molecular biologygeneral chemistrygeneral physics and astronomybiochemistry, genetics and molecular biology(all)chemistry(all)physics and astronomy(all) ??
ID Code:
200980
Deposited By:
Deposited On:
11 Aug 2023 16:00
Refereed?:
Yes
Published?:
Published
Last Modified:
16 Jul 2024 12:05