A small-molecule inhibitor of the BRCA2-RAD51 interaction modulates RAD51 assembly and potentiates DNA damage-induced cell death

Scott, Duncan E. and Francis-Newton, Nicola J. and Marsh, May E. and Coyne, Anthony G. and Fischer, Gerhard and Moschetti, Tommaso and Bayly, Andrew R. and Sharpe, Timothy D. and Haas, Kalina T. and Barber, Lorraine and Valenzano, Chiara R. and Srinivasan, Rajavel and Huggins, David J. and Lee, Miyoung and Emery, Amy and Hardwick, Bryn and Ehebauer, Matthias and Dagostin, Claudio and Esposito, Alessandro and Pellegrini, Luca and Perrior, Trevor and McKenzie, Grahame and Blundell, Tom L. and Hyvönen, Marko and Skidmore, John and Venkitaraman, Ashok R. and Abell, Chris. (2021) A small-molecule inhibitor of the BRCA2-RAD51 interaction modulates RAD51 assembly and potentiates DNA damage-induced cell death. Cell chemical biology, 28 (6). pp. 835-847.e5.

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Official URL: https://edoc.unibas.ch/84033/

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BRCA2 controls RAD51 recombinase during homologous DNA recombination (HDR) through eight evolutionarily conserved BRC repeats, which individually engage RAD51 via the motif Phe-x-x-Ala. Using structure-guided molecular design, templated on a monomeric thermostable chimera between human RAD51 and archaeal RadA, we identify CAM833, a 529 Da orthosteric inhibitor of RAD51:BRC with a K; d; of 366 nM. The quinoline of CAM833 occupies a hotspot, the Phe-binding pocket on RAD51 and the methyl of the substituted α-methylbenzyl group occupies the Ala-binding pocket. In cells, CAM833 diminishes formation of damage-induced RAD51 nuclear foci; inhibits RAD51 molecular clustering, suppressing extended RAD51 filament assembly; potentiates cytotoxicity by ionizing radiation, augmenting 4N cell-cycle arrest and apoptotic cell death and works with poly-ADP ribose polymerase (PARP)1 inhibitors to suppress growth in BRCA2-wildtype cells. Thus, chemical inhibition of the protein-protein interaction between BRCA2 and RAD51 disrupts HDR and potentiates DNA damage-induced cell death, with implications for cancer therapy.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Services Biozentrum > Biophysics Facility (Sharpe)
UniBasel Contributors:Sharpe, Timothy
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Cell Press
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:06 Sep 2021 10:16
Deposited On:06 Sep 2021 10:16

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