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August 14, 2020
Small molecule inhibitors of the transcription factor Brd4 are currently in clinical trials as potent anti-cancer drugs. These agents work by blocking the expression of cancer-causing genes that are driven by the oncogene Myc. Surprisingly, however, Brd4 inhibitors appear to have strong anti-tumor effects even in some tumors that are not driven by the Myc oncogene, but the reasons for this Myc-independent anti-tumor effect has remained unclear.
New research from the Yaffe lab appearing in Nature Communications now shows that in highly proliferative tumor cells, Brd4 function is necessary to block collisions on genomic DNA between sites of RNA transcription and DNA replication. In the absence of Brd4, the molecular machinery that makes RNA collides with different machinery trying to copy the DNA, causing double stranded DNA breaks. They found that cancer cells without BRD4 accumulate R loops—hybrid structures of RNA and DNA that naturally form during transcription—resulting in transcription-replication collisions and DNA damage. Loss of BRD4 also leads to decreased transcription of genes involved in DNA damage response signaling, and thus a decreased ability to repair DNA damage. The continued replication of cells with R loop-damaged DNA results in increased genome instability and cell death. The findings may help researchers design new combination therapies that take advantage of BRD4’s unique role in blocking DNA damage specifically in oncogenic tumor cells.
This work was supported in part by the Koch Institute Frontier Research Program, the Koch Institute - Dana-Farber/Harvard Cancer Center Bridge Project, the MIT Center for Precision Cancer Medicine, and a Koch Institute Quinquennial Cancer Research Fellowship.