BRD4 prevents the accumulation of R-loops and protects against transcription–replication collision events and DNA damage
© 2020, The Author(s). Proper chromatin function and maintenance of genomic stability depends on spatiotemporal coordination between the transcription and replication machinery. Loss of this coordination can lead to DNA damage from increased transcription-replication collision events. We report that...
| Main Authors: | , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Springer Science and Business Media LLC
2021
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| Online Access: | https://hdl.handle.net/1721.1/134408 |
| _version_ | 1811090821485690880 |
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| author | Lam, Fred C Kong, Yi Wen Huang, Qiuying Vu Han, Tu-Lan Maffa, Amanda D Kasper, Ekkehard M Yaffe, Michael B |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Lam, Fred C Kong, Yi Wen Huang, Qiuying Vu Han, Tu-Lan Maffa, Amanda D Kasper, Ekkehard M Yaffe, Michael B |
| author_sort | Lam, Fred C |
| collection | MIT |
| description | © 2020, The Author(s). Proper chromatin function and maintenance of genomic stability depends on spatiotemporal coordination between the transcription and replication machinery. Loss of this coordination can lead to DNA damage from increased transcription-replication collision events. We report that deregulated transcription following BRD4 loss in cancer cells leads to the accumulation of RNA:DNA hybrids (R-loops) and collisions with the replication machinery causing replication stress and DNA damage. Whole genome BRD4 and γH2AX ChIP-Seq with R-loop IP qPCR reveals that BRD4 inhibition leads to accumulation of R-loops and DNA damage at a subset of known BDR4, JMJD6, and CHD4 co-regulated genes. Interference with BRD4 function causes transcriptional downregulation of the DNA damage response protein TopBP1, resulting in failure to activate the ATR-Chk1 pathway despite increased replication stress, leading to apoptotic cell death in S-phase and mitotic catastrophe. These findings demonstrate that inhibition of BRD4 induces transcription-replication conflicts, DNA damage, and cell death in oncogenic cells. |
| first_indexed | 2024-09-23T14:52:29Z |
| format | Article |
| id | mit-1721.1/134408 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T14:52:29Z |
| publishDate | 2021 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1344082023-12-19T20:41:15Z BRD4 prevents the accumulation of R-loops and protects against transcription–replication collision events and DNA damage Lam, Fred C Kong, Yi Wen Huang, Qiuying Vu Han, Tu-Lan Maffa, Amanda D Kasper, Ekkehard M Yaffe, Michael B Koch Institute for Integrative Cancer Research at MIT Center for Precision Cancer Medicine Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Biological Engineering © 2020, The Author(s). Proper chromatin function and maintenance of genomic stability depends on spatiotemporal coordination between the transcription and replication machinery. Loss of this coordination can lead to DNA damage from increased transcription-replication collision events. We report that deregulated transcription following BRD4 loss in cancer cells leads to the accumulation of RNA:DNA hybrids (R-loops) and collisions with the replication machinery causing replication stress and DNA damage. Whole genome BRD4 and γH2AX ChIP-Seq with R-loop IP qPCR reveals that BRD4 inhibition leads to accumulation of R-loops and DNA damage at a subset of known BDR4, JMJD6, and CHD4 co-regulated genes. Interference with BRD4 function causes transcriptional downregulation of the DNA damage response protein TopBP1, resulting in failure to activate the ATR-Chk1 pathway despite increased replication stress, leading to apoptotic cell death in S-phase and mitotic catastrophe. These findings demonstrate that inhibition of BRD4 induces transcription-replication conflicts, DNA damage, and cell death in oncogenic cells. 2021-10-27T20:04:52Z 2021-10-27T20:04:52Z 2020 2021-08-04T15:18:27Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/134408 en 10.1038/S41467-020-17503-Y Nature Communications Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Springer Science and Business Media LLC Nature |
| spellingShingle | Lam, Fred C Kong, Yi Wen Huang, Qiuying Vu Han, Tu-Lan Maffa, Amanda D Kasper, Ekkehard M Yaffe, Michael B BRD4 prevents the accumulation of R-loops and protects against transcription–replication collision events and DNA damage |
| title | BRD4 prevents the accumulation of R-loops and protects against transcription–replication collision events and DNA damage |
| title_full | BRD4 prevents the accumulation of R-loops and protects against transcription–replication collision events and DNA damage |
| title_fullStr | BRD4 prevents the accumulation of R-loops and protects against transcription–replication collision events and DNA damage |
| title_full_unstemmed | BRD4 prevents the accumulation of R-loops and protects against transcription–replication collision events and DNA damage |
| title_short | BRD4 prevents the accumulation of R-loops and protects against transcription–replication collision events and DNA damage |
| title_sort | brd4 prevents the accumulation of r loops and protects against transcription replication collision events and dna damage |
| url | https://hdl.handle.net/1721.1/134408 |
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