2. Academic Validation
  3. BRD4 prevents the accumulation of R-loops and protects against transcription-replication collision events and DNA damage

BRD4 prevents the accumulation of R-loops and protects against transcription-replication collision events and DNA damage

  • Nat Commun. 2020 Aug 14;11(1):4083. doi: 10.1038/s41467-020-17503-y.
Fred C Lam  # 1 2 3,  Yi Wen Kong  # 4 5,  Qiuying Huang 4,  Tu-Lan Vu Han 4,  Amanda D Maffa 4,  Ekkehard M Kasper 6,  Michael B Yaffe 7 8 9 10
Affiliations

Affiliations

  • 1 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA, 02139, USA. lamf9@mcmaster.ca.
  • 2 Center for Precision Cancer Medicine, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA, 02139, USA. lamf9@mcmaster.ca.
  • 3 Faculty of Health Sciences, Division of Neurosurgery, Hamilton General Hospital, McMaster University, 237 Barton St E, Hamilton, ON, L8L 2X2, Canada. lamf9@mcmaster.ca.
  • 4 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA, 02139, USA.
  • 5 Center for Precision Cancer Medicine, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA, 02139, USA.
  • 6 Faculty of Health Sciences, Division of Neurosurgery, Hamilton General Hospital, McMaster University, 237 Barton St E, Hamilton, ON, L8L 2X2, Canada.
  • 7 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA, 02139, USA. myaffe@mit.edu.
  • 8 Center for Precision Cancer Medicine, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA, 02139, USA. myaffe@mit.edu.
  • 9 Departments of Biology and Bioengineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. myaffe@mit.edu.
  • 10 Beth Israel Deaconess Medical Center, Department of Surgery, Harvard Medical School, Boston, MA, 02215, USA. myaffe@mit.edu.
  • # Contributed equally.
PMID: 32796829 DOI: 10.1038/s41467-020-17503-y
Abstract

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.

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