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

被引：243

作者：

Kotsantis, Panagiotis ^{[1
]}

Silva, Lara Marques ^{[2
]}

Irmscher, Sarah ^{[2
]}

Jones, Rebecca M. ^{[1
]}

Folkes, Lisa ^{[3
]}

Gromak, Natalia ^{[2
]}

Petermann, Eva ^{[1
]}

机构：

[1] Univ Birmingham, Inst Canc & Genom Sci, Birmingham B15 2TT, W Midlands, England

[2] Univ Oxford, Sir William Dunn Sch Pathol, South Parks Rd, Oxford OX1 3RE, England

[3] Univ Oxford, Dept Oncol, CRUK MRC Oxford Inst Radiat Oncol, Old Rd Campus Res Bldg,Roosevelt Dr, Oxford OX3 7DQ, England

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

英国医学研究理事会;

关键词：

TATA-BINDING PROTEIN; ONCOGENE-INDUCED SENESCENCE; RNA-POLYMERASE-III; GENOMIC INSTABILITY; DNA-REPLICATION; C-MYC; CHROMOSOMAL INSTABILITY; CELL-GROWTH; STEM-CELLS; IN-VIVO;

D O I：

10.1038/ncomms13087

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 HRAS(V12) 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 HRAS(V12), 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.

引用

页数：13

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