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Title: | A small-molecule inhibitor of the BRCA2-RAD51 interaction modulates RAD51 assembly and potentiates DNA damage-induced cell death |
Authors: | Scott, DE Francis-Newton, NJ Marsh, ME Coyne, AG Fischer, G Moschetti, T Bayly, AR Sharpe, TD Haas, KT Barber, L Valenzano, CR Srinivasan, R Huggins, DJ Lee, M Emery, A Hardwick, B Ehebauer, M Dagostin, C Esposito, A Pellegrini, L Perrior, T McKenzie, G Blundell, TL Hyvönen, M Skidmore, J Venkitaraman, AR Abell, C |
Keywords: | RAD51;homologous recombination;BRCA2;DNA repair;structure-guided drug discovery;protein-protein interaction inhibition;RAD51 inhibitor;radiosensitizer;cancer therapy |
Issue Date: | 3-Mar-2021 |
Publisher: | Elsevier Ltd. |
Citation: | Scott, D.E. et al. (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 (+ e1 - e5). doi: 10.1016/j.chembiol.2021.02.006. |
Abstract: | Copyright © 2021 The Authors. 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 Kd 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. |
Description: | Supplemental information: Document S1. Figures S1–S5, Tables S1–S3, and Methods S1 available at: https://www.cell.com/cms/10.1016/j.chembiol.2021.02.006/attachment/3e31e265-54fc-4337-ac40-861ecb85706e/mmc1.pdf (1.44 MB) |
URI: | https://bura.brunel.ac.uk/handle/2438/25425 |
DOI: | https://doi.org/10.1016/j.chembiol.2021.02.006 |
ISSN: | 2451-9456 |
Appears in Collections: | Dept of Life Sciences Research Papers |
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FullText.pdf | Copyright © 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/). | 4.97 MB | Adobe PDF | View/Open |
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