Abstract

Fabrizio d’Adda di Fagagna 1, 2

1 IFOM – the FIRC Institute for Molecular Oncology Foundation, Milan, Italy 2 IGM -CNR – Istituto di Genetica Molecolare-Consiglio Nazionale delle Ricerche, Pavia, Italy

We previously reported that DNA double-strand breaks (DSBs) trigger the synthesis by RNA polymerase II of damage-induced long non-coding RNA (dilncRNA) that can be processed into shorter DNA damage response RNAs (DDRNAs). Such transcripts are essential for full DDR activation and their inhibition by antisense oligonucleotides (ASO) allows site-specific inhibition of DNA damage signalling and repair (Francia et al Nature 2012, Michelini et al Nature Cell Biology 2017, D’Alessandro et al Nature Communications 2018). We recently discovered that such transcriptional events depend on the assembly of seemingly fully functional transcriptional promoters that include a complete RNA polymerase II preinitiation complex (PIC). Absence or inactivation of any of these factors causes a reduction in the activation of the DNA damage response (DDR) both in cells and in an in vitro system that reconstitutes DDR activation events on nucleosomes. Importantly, dilncRNAs drive molecular crowding of DDR proteins, such as 53BP1, into globular structures that exhibit liquid–liquid phase-separation condensate properties (Pessina et al Nature Cell Biology 2019).

Telomeres, the ends of linear chromosomes, progressively accumulate DNA damage during physiological and pathological aging. We recapitulated the above-described events at damaged telomeres (Rossiello et al. Nature Communications 2017) and demonstrated that, in independent animal models of accelerated aging, specific DDR inhibition at telomeres by ASO improves aging’s detrimental phenotypes and extends lifespan (Aguado et al. Nature Communications 2019). We are now extending these observations in a number of models of age-related human diseases

More recently we demonstrated that a subset of cancer types is selectively sensitive to the treatment with this ASO -mediated approach.