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, Panagiotis; Marques Silva, Lara; Irmscher, Sarah; Jones, Rebecca; Folkes, Lisa; Gromak, Natalia; Petermann, Eva.

In: Nature Communications, Vol. 7, 13087, 11.10.2016.

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@article{a04950da9f614395b40edd335255316a,
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 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.",
keywords = "RAS, oncogenes, TBP, R-loops, RNA/DNA hybrids, replication stress, DNA damage, genome instability",
author = "Panagiotis Kotsantis and {Marques Silva}, Lara and Sarah Irmscher and Rebecca Jones and Lisa Folkes and Natalia Gromak and Eva Petermann",
year = "2016",
month = oct,
day = "11",
doi = "10.1038/ncomms13087",
language = "English",
volume = "7",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Springer",

}

RIS

TY - JOUR

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

AU - Kotsantis, Panagiotis

AU - Marques Silva, Lara

AU - Irmscher, Sarah

AU - Jones, Rebecca

AU - Folkes, Lisa

AU - Gromak, Natalia

AU - Petermann, Eva

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 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.

AB - 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.

KW - RAS

KW - oncogenes

KW - TBP

KW - R-loops

KW - RNA/DNA hybrids

KW - replication stress

KW - DNA damage

KW - genome instability

U2 - 10.1038/ncomms13087

DO - 10.1038/ncomms13087

M3 - Article

VL - 7

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 13087

ER -