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

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Increased global transcription activity as a mechanism of replication stress in cancer. / Kotsantis, P.; Silva, L.M.; Irmscher, S. et al.
In: Nature Communications, Vol. 7, 13087, 11.10.2016.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Harvard

Kotsantis, P, Silva, LM, Irmscher, S, Jones, RM, Folkes, L, Gromak, N & Petermann, E 2016, 'Increased global transcription activity as a mechanism of replication stress in cancer', Nature Communications, vol. 7, 13087. https://doi.org/10.1038/ncomms13087

APA

Kotsantis, P., Silva, L. M., Irmscher, S., Jones, R. M., Folkes, L., Gromak, N., & Petermann, E. (2016). Increased global transcription activity as a mechanism of replication stress in cancer. Nature Communications, 7, Article 13087. https://doi.org/10.1038/ncomms13087

Vancouver

Kotsantis P, Silva LM, Irmscher S, Jones RM, Folkes L, Gromak N et al. Increased global transcription activity as a mechanism of replication stress in cancer. Nature Communications. 2016 Oct 11;7:13087. doi: 10.1038/ncomms13087

Author

Kotsantis, P. ; Silva, L.M. ; Irmscher, S. et al. / Increased global transcription activity as a mechanism of replication stress in cancer. In: Nature Communications. 2016 ; Vol. 7.

Bibtex

@article{fd7855c42af64e36b6c7f39922ca8c75,
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 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.",
author = "P. Kotsantis and L.M. Silva and S. Irmscher and R.M. Jones and L. Folkes and N. Gromak and E. Petermann",
year = "2016",
month = oct,
day = "11",
doi = "10.1038/ncomms13087",
language = "English",
volume = "7",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

RIS

TY - JOUR

T1 - Increased global transcription activity as a mechanism of replication stress in cancer

AU - Kotsantis, P.

AU - Silva, L.M.

AU - Irmscher, S.

AU - Jones, R.M.

AU - Folkes, L.

AU - Gromak, N.

AU - Petermann, E.

PY - 2016/10/11

Y1 - 2016/10/11

N2 - 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.

AB - 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.

U2 - 10.1038/ncomms13087

DO - 10.1038/ncomms13087

M3 - Journal article

VL - 7

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 13087

ER -