Increased global transcription activity as a mechanism of replication stress in cancer.
Increased global transcription activity as a mechanism of replication stress in cancer.
复制标题
DOI：
10.1038/ncomms13087
复制
发表时间：
2016-10-11
影响因子：
16.6
通讯作者：
Petermann, Eva
中科院分区：
文献类型：
--
作者：
Kotsantis, Panagiotis;Silva, Lara Marques;Irmscher, Sarah;Jones, Rebecca M.;Folkes, Lisa;Gromak, Natalia;Petermann, Eva
癌症是一种与基因组不稳定相关的疾病，通常是由癌基因激活引起的。这反过来又导致过度增殖和复制压力。然而，致癌基因诱导的复制应激的分子机制仍然知之甚少。癌基因如HRASV12通过上调一般转录因子刺激RNA合成来促进增殖。在这里，我们研究这种转录的增加是否成为癌基因诱导的复制应激的基础。我们发现，在过表达HRASV12的细胞中，一般转录因子TATA-box结合蛋白（TBP）的表达升高导致RNA合成增加，这与r环积累一起导致复制叉减慢和DNA损伤。此外，仅TBP的过表达就会引起癌基因诱导的复制应激的标志，包括复制叉减慢、DNA损伤和衰老。因此，我们揭示了转录增加可能是癌基因诱导的DNA损伤的一种机制，提供了癌症中转录机制上调和基因组不稳定性之间的分子联系。癌细胞以高速率增殖并引起复制压力。在这里，作者表明，这可能是癌基因诱导的更高转录活性的结果，通过增加RNA合成和r环积累，导致复制叉减慢和DNA损伤。
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. Cancer cells proliferate at high rates and incur replication stress. Here, the authors show that this can be the consequence of oncogene-induced higher transcriptional activity, which, through increased RNA synthesis and R-loop accumulation, results in replication fork slowing and DNA damage.
登录
查看更多内容
影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
影响因子：
64.8
作者：
Di Micco, Raffaella;Fumagalli, Marzia;di Fagagna, Fabrizio d'Adda
通讯作者：
di Fagagna, Fabrizio d'Adda
影响因子：
64.8
作者：
Burrell RA;McClelland SE;Endesfelder D;Groth P;Weller MC;Shaikh N;Domingo E;Kanu N;Dewhurst SM;Gronroos E;Chew SK;Rowan AJ;Schenk A;Sheffer M;Howell M;Kschischo M;Behrens A;Helleday T;Bartek J;Tomlinson IP;Swanton C
通讯作者：
Swanton C
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
64.8
作者：
Dominguez-Sola, David;Ying, Carol Y.;Dalla-Favera, Riccardo
通讯作者：
Dalla-Favera, Riccardo