DNA damage accumulation is a key feature of the aging process
by Prof. Fabrizio d’Adda di Fagagna of the IFOM (Italy)
DNA damage accumulation at telomeres and their shortening below a critical length engage the DNA damage response (DDR) machinery, leading to cellular senescence and apoptosis. The contribution of telomeric DDR activation in vivo in natural aging and in aging-related pathologies remains unprobed due to the lack of approaches to selectively inhibit DDR at telomeres only.
We previously reported that DNA double-strand breaks (DSBs) trigger the synthesis of damage-induced long non-coding RNA (dilncRNA) that can be processed into shorter DNA damage response RNAs (DDRNAs) (Francia et al Nature 2012, Michelini et al Nature Cell Biology 2017, Pessina et al Nature Cell Biology 2019 ). Such transcripts are essential for full DNA damage response (DDR) activation and their inhibition by antisense oligonucleotides (ASO) allows site-specific DDR inhibition. Dysfunctional telomeres resemble DSBs (d’adda di Fagagna et al Nature 2003, Fumagalli et al Nature Cell Biology 2012) and indeed telomere uncapping leads to telomeric dilncRNAs and DDRNAs accumulation. ASOs against such telomeric dilncRNAs and DDRNAs inhibit DDR activation at dysfunctional telomeres in cultured cells and in vivo in mice (Rossiello et al. Nature Communications 2017).
This recently-acuired ability to specifically inhibit DDR activation at telomeres allows for the first time to control telomeric DDR and cellular senescence in physiological and pathological contexts, including ageing diseases and progerias.
Hutchinson-Gilford Progeria Syndrome (HGPS) cells show telomere dysfunction and DDR activation among other detrimental phenotypes. We demonstrated that telomeric ASO treatment in vitro of HGPS patients’ fibroblasts extends their proliferative capacity. In a conditional HGPS mouse model with the common human mutation, LMNA c.1824C>T, telomeric ASO treatment improves tissue homeostasis, reduces inflammation and significantly extends survival (Aguado et al Nature Communications 2019). In telomerase knockout (G3 Terc KO) mice, we will show how systemic treatment with telomeric ASO has an important impact on several organs, as assessed by histopathological analyses and profiling of several markers. In a zebrafish strain carrying a mutation in the telomerase gene, we will also describe the impact of telomeric DDR inhibition by ASO on the reduction of aberrant phenotypes and on extended survival.
Overall, these results will show that telomeric DDR inhibition by ASO technologies allows selective DDR inhibition, improvement of pathological aging phenotypes and extend lifespan in two animal species carrying distinct genetic defects.
Speaker invited by DCEXS
The colloquium is part of the BIST Master of Research curriculum but is also open and free for anyone interested in participating.
The session will be hosted through Zoom online conference application. If you have not used this platform previously, you will be prompted to download the software to access the meeting (the process is automatic and does not require more than one minute).
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