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Monika Gullerova

The role of RNA in DNA damage response

The RNAse III-type endonuclease Dicer is a key component of the human RNA interference (RNAi) pathway and is well known for its role in microRNA production. The cytoplasmic function of Dicer is well documented, but its nuclear role remains unclear. We showed that human Dicer is present in the nuclei, processing endogenous double-stranded RNA (dsRNA) derived from the sites of overlapping transcription. In the absence of Dicer, endo-dsRNA escapes to cytoplasm, where it activates interferon response and leads to cell death (NSMB, 2014). Recent findings suggest that non-canonical Dicer generates small non-coding RNA to mediate the DNA damage response (DDR). We show that human Dicer is phosphorylated in the platform-PAZ-connector helix cassette (Ser1016) upon DNA damage. This modification triggers nuclear localisation of phosphorylated Dicer (p-Dicer) and its recruitment to double-strand breaks (DSBs) in a transcription and dsRNA dependent manner. Dicer depletion causes persistence of DNA damage and delayed DDR. We place nuclear Dicer in the context of DDR by demonstrating a DNA damage-inducible phospho-switch that promotes localised dsRNA processing (submitted).

      Cohesin is essential not only for well-known sister chromatid cohesion, but also for the regulation of gene expression and DNA repair. We showed that sites of cohesion on chromosomal arms overlap with highly expressed genes and induction of transcription results in de novo cohesion establishment in S. pombe. We extend our data to human cells, suggesting that transcription requirement for cohesion establishment might be a general mechanism (NAR, 2016).

      We are investigating the interplay between RNAi, transcription and Cohesin recruitment to the sites of DNA damage. All these factors possess primary function including gene silencing, gene expression and chromosome segregation, but they might also play a role in DDR exhibiting their non-canonical functions in orchestrating efficient DNA repair.