THE ROLE OF TELOMERIC RNA AT DYSFUNCTIONAL TELOMERES AND ITS IMPACT ON SENESCENCE AND AGING

A novel class of small non-coding RNAs discovered in our laboratory, termed DNA damage response RNAs (DDRNAs), has been demonstrated to be generated upon DNA double strand break (DSB) induction, and to be necessary for full DNA Damage Response (DDR) activation. DDRNAs are generated following DSB induction upon transcription of the damaged locus and the synthesis of an RNA precursor further processed by the endoribonucleases DICER and DROSHA. The aim of this PhD dissertation was to investigate the mechanism underlying DDRNA-dependent DDR activation specifically at telomeres, important chromosomal regions required for genomic stability that, if disrupted, are associated with aging-related diseases. In this dissertation, I show that telomere dysfunction, like DSBs, induces the transcription of telomeric DDRNAs and their precursors from both DNA strands of the telomere. Such transcripts are necessary for DDR activation and maintenance at dysfunctional telomeres. Most importantly, the use of sequence-specific antisense oligonucleotides (ASOs) allows the inhibition of telomere transcripts’ functions, thereby specifically inhibiting telomeric DDR. Telomere dysfunction is rising as a key feature in Hutchinson–Gilford Progeria Syndrome (HGPS) and other premature aging syndromes. Here I show that progerin, the protein whose expression causes HGPS, induces the transcription of telomere transcripts, both in vitro and in vivo. Furthermore, signaling inhibition of progerin-driven telomere dysfunction improves the growth potential of progerin-expressing cells. Finally, this inhibition also increases the lifespan of an HGPS mouse model, opening the possibility for the use of this approach as a viable therapy to treat HGPS.