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bioRxiv · 10.1101/2021.01.08.425946

Dicer promotes genome stability via the bromodomain transcriptional co-activator Brd4.

Gutbrod, M.·Roche, B.·Steinberg, J.·Lakhani, A.·Chang, K.·Schorn, A.·Martienssen, R. A.
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Abstract

RNA interference is essential for transcriptional silencing and genome stability, but conservation of this role in mammals has been difficult to demonstrate. Dicer1-/- mouse embryonic stem cells have microRNA-independent proliferation defects, and we conducted a CRISPR-Cas9 screen to restore viability. We identified suppressor mutations in transcriptional activators, H3K9 methyltransferases, and chromosome segregation factors, strongly resembling Dicer suppressors in fission yeast. Suppressors rescued chromosomal defects, and reversed strand-specific transcription of major satellite repeats in Dicer1-/-. The strongest suppressors were in Brd4, and in the transcriptional elongator/histone acetyltransferase Elp3. Using viable mutants and pharmaceutical inhibitors, we demonstrate that deletion of specific residues in Brd4 rescue genome instability defects of Dicer1-/- in both mammalian cells and fission yeast, implicating Dicer in coordinating transcription and replication of satellite repeats. SummaryReplication and segregation defects in Dicer1-/- stem cells depend on centromeric transcription by Brd4, and are deeply conserved in fission yeast.

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Gutbrod, M., Roche, B., Steinberg, J., Lakhani, A., Chang, K., Schorn, A., Martienssen, R. A.. 2021-01-08. Dicer promotes genome stability via the bromodomain transcriptional co-activator Brd4.. https://doi.org/10.1101/2021.01.08.425946

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