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Scientific result | Article | DNA | Structural biology
In an article published in the journal Nucleic Acids Research, scientists from the I2BC (genome integrity team at B3S), the lPBS and the Institute for Structural and Chemical Biology (University of Leicester, UK) demonstrate how phytic acid, a product of cellular metabolism, stabilises the assembly of a complex enabling the repair of DNA breaks in humans.
Tumours are made up of
cells that proliferate excessively and
escape programmed cell death (apoptosis). One way of inducing the death of a tumour cell is
to break its DNA sufficiently. This is done in
radiotherapy and with certain chemotherapies. But tumour cells that have not been eliminated are capable of repairing the breaks in their DNA and can therefore proliferate again. A
complementary strategy is therefore
to act on DNA repair mechanisms.
Human cells repair their DNA in two different ways:
The NHEJ pathway is the dominant repair system. After radiotherapy, tumour cells absolutely need this repair pathway, unlike normal cells. NHEJ is initiated by the Ku70/Ku80 protein complex, which rapidly encircles the ends of the break and acts as a tether for the other proteins needed to bind these ends together: DNA-PKc, Lig4, XRCC4 and XLF. The NHEJ system is highly regulated: cofactors, post-translational modifications, metabolites, etc
Around twenty years ago, scientists discovered that a small molecule produced by the body and sometimes used as a food supplement, inositol hexaphosphate (IP6) or phytic acid, binds to the Ku complex and stimulates NHEJ.
Using two techniques for studying proteins at the atomic scale (crystallography and cryo-electron microscopy), researchers from the I2BC (B3S department / INTGEN team, (UMR 9198, CNRS/CEA/UPSaclay, Gif-sur-Yvette), the IPBS (CNRS/Université Paul Sabatier) and the Institute for Structural and Chemical Biology (Leicester) have discovered how IP6 binds to the Ku protein. Biophysical experiments show that the binding of IP6 to Ku stabilises Ku's interaction with DNA and increases the affinity of the XLF protein for Ku. In vitro, in cell cultures, mutations in the IP6-Ku binding site reduce the accumulation of Ku at break sites and the recruitment of XLF to these same sites, thereby reducing the efficiency of the system. In other words, the presence of phytic acid on the Ku protein stimulates the attachment of the XLF protein to the Ku protein, an essential step in effectively sealing the DNA break (see Figure). This work opens up therapeutic prospects by identifying a new area on the Ku protein that could be targeted by small molecules to block break repair in tumour cells.
Antonia Kefala Stavridi, Amandine Gontier, Vincent Morin, Philippe Frit, Virginie Ropars, Nadia Barboule, Carine Racca, Sagun Jonchhe, Michael J. Morten, Jessica Andreani, Alexey Rak, Pierre Legrand, Alexa Bourand-Plantefol, Steven W. Hardwick, Dimitri Y. Chirgadze, Paul Davey, Taiana Maia De Oliveira, Eli Rothenberg, Sébastien Britton*, Patrick Calsou*, Tom L. Blundell*, Paloma F. Varela*, Amanda K. Chaplin* and J.B Charbonnier*. Structural and functional basis of inositol hexaphosphate stimulation of NHEJ through stabilization of Ku-XLF interaction. | Nucleic Acids Research, Volume 51, Issue 21, 27 November 2023, Pages 11732–11747, 2023, https://doi.org/10.1093/nar/gkad863
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.