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.

中文翻译：

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Dicer通过溴结构域转录共激活因子Brd4促进基因组稳定性。

RNA干扰对于转录沉默和基因组稳定性是必不可少的，但是很难证明这种作用在哺乳动物中的保持作用。Dicer1-/-小鼠胚胎干细胞具有不依赖microRNA的增殖缺陷，我们进行了CRISPR-Cas9筛选以恢复活力。我们在转录激活因子，H3K9甲基转移酶和染色体分离因子中发现了抑制子突变，非常类似于裂变酵母中的Dicer抑制子。抑制因子挽救了染色体缺陷，并逆转了Dicer1-/-中主要卫星重复序列的链特异性转录。最强的抑制剂在Brd4和转录延伸剂/组蛋白乙酰转移酶Elp3中。使用可行的突变体和药物抑制剂，