TeloRNAging SIGNED

Project "TeloRNAging" data sheet

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 Project objective

Genome instability is a hallmark of cellular and organismal aging. Cells evolved a prompt set of actions known as the DNA damage response (DDR) to preserve genome integrity. Until very recently, DDR pathways have been studied as networks of interacting proteins only. We discovered that the full activation of the DDR pathways depends also on long and short damage-induced non coding RNA synthesised from exposed DNA ends of DNA double-strand breaks (DSB). Inhibitory antisense oligonucleotides (ASO) targeting such non coding RNAs in a sequence-specific manner prevent DDR activation at individual genomic sites. Telomeres, the ends of linear chromosomes, are the best characterized genomic sites of preferential DDR activation during aging. Also telomere dysfunction, similarly to DSB, triggers the synthesis of non coding RNA and ASO against them prevent DDR activation at dysfunctional telomeres in cultured cells and in mice. We plan to determine the mechanisms that unleash ncRNA biogenesis upon telomere dysfunction and identify their mechanisms of action in DDR activation. By exploiting our unprecedented ability to inhibit DDR selectively at telomeres, we will determine the specific contribution of telomeric DDR activation to the detrimental phenotypes associated with aging-related disorders.