The integrity of our genome has to be maintained ed to prevent accumulation of harmful mutations, or cell death. This is even more needed in tumor cells where breaks in DNA occur at higher frequency. This feature of cancer cells can be exploited to set up therapeutic strategies based on inhibition of DNA repair with the aim to induce cell death. The drugs used so far to strike this "Achilles heel" of cancer cells block the enzymatic activity of essential DNA repair proteins, such as ATM, ATR or PARP, therefore indiscriminately hamper DNA repair pathways both in healthy and in cancer cells, causing serious adverse effects. The challenge is to make this therapeutic approach more specific and less toxic.
A promising solution comes from a study by the group of Fabrizio d'Adda di Fagagna, a researcher at IGM and IFOM in Milan, published last week in the prestigious journal Nature Cell Biology, with the IFOM's post-doc Flavia Michelini as first author. This work is the development of a previous observation by the same group concerning the crucial role of some small non-coding RNAs, the DDRNA, in signaling and repairing DNA lesions. The previous article was published in Nature in 2012 with the researcher of IGM Sofia Francia as first author. Now, in collaboration with the University of Michigan and the Mechanobiology Institute in Singapore, these scientists have shown that DNA breakage elicits the production of long non-coding RNAs, then processed into DDRNA, whose sequence matches that of the damaged site. This discovery suggests a more selective therapeutic approach that targets RNAs synthesized at sites of damage thus preventing repair of specific lesions without affecting DNA repair elsewhere in the genome. To achieve this goal, scientists took advantage of an innovative class of molecules called 'antisense oligonucleotides' that only affect complementary RNAs. This approach can be applied to selectively hit tumor cells, making them unable to repair DNA damages at specific genomic regions and consequently affecting their survival and proliferation. Antisense molecules represent an emerging and promising class of molecules suitable for more effective and less toxic therapeutic approaches in the so called "precision medicine".
Damage-induced lncRNAs control the DNA damage response through interaction with DDRNAs at individual double-strand breaks.
Michelini F, Pitchiaya S, Vitelli V, Sharma S, Gioia U, Pessina F, Cabrini M, Wang Y, Capozzo I, Iannelli F, Matti V, Francia S, Shivashankar GV, Walter NG, d'Adda di Fagagna F.
Nat Cell Biol. 2017 Dec;19(12):1400-1411. doi: 10.1038/ncb3643. Epub 2017 Nov 27.
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