Increased global transcription activity as a mechanism of replication stress in cancer
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 HRA...
| Հիմնական հեղինակներ: | , , , , , , |
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| Ձևաչափ: | Journal article |
| Լեզու: | English |
| Հրապարակվել է: |
Nature Publishing Group
2016
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| _version_ | 1826296977589010432 |
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| author | Kotsantis, P Silva, L Irmscher, S Jones, R Folkes, L Gromak, N Petermann, E |
| author_facet | Kotsantis, P Silva, L Irmscher, S Jones, R Folkes, L Gromak, N Petermann, E |
| author_sort | Kotsantis, P |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T04:24:36Z |
| format | Journal article |
| id | oxford-uuid:cc301b51-f4c8-4d88-b28f-896d7030f065 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:24:36Z |
| publishDate | 2016 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:cc301b51-f4c8-4d88-b28f-896d7030f0652022-03-27T07:20:09ZIncreased global transcription activity as a mechanism of replication stress in cancerJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:cc301b51-f4c8-4d88-b28f-896d7030f065EnglishSymplectic Elements at OxfordNature Publishing Group2016Kotsantis, PSilva, LIrmscher, SJones, RFolkes, LGromak, NPetermann, ECancer 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. |
| spellingShingle | Kotsantis, P Silva, L Irmscher, S Jones, R Folkes, L Gromak, N Petermann, E Increased global transcription activity as a mechanism of replication stress in cancer |
| title | Increased global transcription activity as a mechanism of replication stress in cancer |
| title_full | Increased global transcription activity as a mechanism of replication stress in cancer |
| title_fullStr | Increased global transcription activity as a mechanism of replication stress in cancer |
| title_full_unstemmed | Increased global transcription activity as a mechanism of replication stress in cancer |
| title_short | Increased global transcription activity as a mechanism of replication stress in cancer |
| title_sort | increased global transcription activity as a mechanism of replication stress in cancer |
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