Batman swoops through Gotham, Supergirl flies over National City, and the Black Panther keeps his keen eyes on Wakanda; every superhero acts as a guardian of the beloved place they call home, protecting from any number of devious and dastardly threats. Now, researchers from the laboratory of Xu Dong Zhang and Mian Wu (Henan Provincial People’s Hospital, Zhengzhou, China) have revealed that a superhero also protects our genome and maintains DNA integrity: the long non-coding RNA (lncRNA) we now know as GUARDIN!
In brief, the authors set out to identify additional lncRNAs induced by the tumor suppressor and DNA damage repair facilitator p53 that help to maintain genome integrity. p53 plays multiple roles in response to threats to genome integrity, including the promotion of cell cycle arrest to allow DNA damage repair or signaling for the apoptosis of cells with severely damaged DNA.
So what fantastical deeds by GUARDIN did the authors discover?
- Employing p53-null human lung adenocarcinoma cells carrying an inducible wild-type p53 expression system, the authors aimed to uncover new p53-responsive lncRNAs
- This approach highlighted the accumulation of the longest isoform of the RP3-510D11.2 lncRNA, which the authors named GUARDIN
- Wild-type p53 expression in several cancer cell lines increases GUARDIN expression via direct binding to the GUARDIN promoter
- Activation of the DNA damage response leads to GUARDIN upregulation both in cancer and normal human cells
- Detailed analysis suggested that GUARDIN promotes survival and proliferation by protecting against the constitutive cellular stresses present in cells, as well as exogenous genotoxic stress, by employing two primary mechanisms:
- miRNA Sponge: GUARDIN prevents the activation of the DNA damage response at telomere ends by sequestering microRNA-23a and thereby promoting the accumulation of its target, the telomeric repeat-binding factor 2 (TRF2), a critical component of the shelterin complex that protects telomere ends
- RNA Scaffold: GUARDIN enhances DNA damage repair by acting as an RNA scaffold to promote the heterodimerization of breast cancer 1 (BRCA1) and BRCA1-associated RING domain protein 1 (BARD1), thereby promoting BRCA1 stability and function
- GUARDIN silencing triggered apoptosis and senescence, but also enhanced the cytotoxicity of exogenous genotoxic stress and inhibited cancer xenograft growth
- Small molecules that block the interaction of GUARDIN with miRNA-23a and BRCA1 may represent a means to improve cancer treatment
What the talented team discovered in this new p53-based study may permit the design of new and more effective anti-cancer therapies, with our new superhero GUARDIN playing the central role.
For more on the heroic deeds of the lncRNA GUARDIN and p53 in defense of our genome, see the accompanying News and Views article, or go straight to the original study at Nature Cell Biology, March 2018.