Abstract
The DNA damage response (DDR) is a set of cellular events that follows the generation of DNA damage. Recently, site-specific small non-coding RNAs, also termed DNA damage response RNAs (DDRNAs), have been shown to play a role in DDR signalling and DNA repair. Dysfunctional telomeres activate DDR in ageing, cancer and an increasing number of identified pathological conditions. Here we show that, in mammals, telomere dysfunction induces the transcription of telomeric DDRNAs (tDDRNAs) and their longer precursors from both DNA strands. DDR activation and maintenance at telomeres depend on the biogenesis and functions of tDDRNAs. Their functional inhibition by sequence-specific antisense oligonucleotides allows the unprecedented telomere-specific DDR inactivation in cultured cells and in vivo in mouse tissues. In summary, these results demonstrate that tDDRNAs are induced at dysfunctional telomeres and are necessary for DDR activation and they validate the viability of locus-specific DDR inhibition by targeting DDRNAs.
Highlights
The DNA damage response (DDR) is a set of cellular events that follows the generation of DNA damage
To study telomeric DDRNAs (tDDRNAs) we employed miScript, a quantitative PCR with reverse transcription (RT–qPCR)-based method[22] developed to detect and quantify small RNAs, and designed primers to selectively amplify either strands of potential tDDRNAs generated at deprotected telomeres: teloC (C-rich strand of tDDRNA) and teloG (G-rich strand of tDDRNA; Supplementary Fig. 1b)
Using a gel-extracted fraction of RNAs shorter than 40 nucleotides—minimizing the contribution of much longer telomeric transcripts, including TERRA18,19,23—we observed an induction of both teloC and teloG RNAs (Fig. 1a), with the potential to form in vivo double-stranded tDDRNA molecules
Summary
The DNA damage response (DDR) is a set of cellular events that follows the generation of DNA damage. Site-specific small non-coding RNAs, termed DNA damage response RNAs (DDRNAs), have been shown to play a role in DDR signalling and DNA repair. Their functional inhibition by sequence-specific antisense oligonucleotides allows the unprecedented telomere-specific DDR inactivation in cultured cells and in vivo in mouse tissues These results demonstrate that tDDRNAs are induced at dysfunctional telomeres and are necessary for DDR activation and they validate the viability of locus-specific DDR inhibition by targeting DDRNAs. Carmody Road, St Lucia, Queensland 4067, Australia. A class of small non-coding RNAs (ncRNAs), termed DNA damage response RNAs (DDRNAs), has been shown to be generated on transcription of the damaged locus following DSB induction and processed by the endoribonucleases DICER and DROSHA3–5. We provide evidence that both strands of deprotected telomeres are transcribed to generate telomeric DDRNAs (tDDRNAs) and their precursors, whose inhibition leads to a reduction in the DDR activation at dysfunctional telomeres in living cells and in vivo
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