BRD4 prevents the accumulation of R-loops and protects against transcription–replication collision events and DNA damage
Name
s41467-020-17503-y.pdf
Description
Published version
Size
3.52 MB
Format
Adobe PDF
Checksum (MD5)
d6a70b67722bb600d9ca7dcfe84889fa
Author(s)
Lam, Fred C
Kong, Yi Wen
Huang, Qiuying
Vu Han, Tu-Lan
Maffa, Amanda D
Kasper, Ekkehard M
Yaffe, Michael B
Date Issued
2020
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Version
Final published version
Abstract
© 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.
MIT Department
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
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1038/S41467-020-17503-Y
