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DC Field | Value | Language |
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dc.contributor.author | Scott, DE | - |
dc.contributor.author | Francis-Newton, NJ | - |
dc.contributor.author | Marsh, ME | - |
dc.contributor.author | Coyne, AG | - |
dc.contributor.author | Fischer, G | - |
dc.contributor.author | Moschetti, T | - |
dc.contributor.author | Bayly, AR | - |
dc.contributor.author | Sharpe, TD | - |
dc.contributor.author | Haas, KT | - |
dc.contributor.author | Barber, L | - |
dc.contributor.author | Valenzano, CR | - |
dc.contributor.author | Srinivasan, R | - |
dc.contributor.author | Huggins, DJ | - |
dc.contributor.author | Lee, M | - |
dc.contributor.author | Emery, A | - |
dc.contributor.author | Hardwick, B | - |
dc.contributor.author | Ehebauer, M | - |
dc.contributor.author | Dagostin, C | - |
dc.contributor.author | Esposito, A | - |
dc.contributor.author | Pellegrini, L | - |
dc.contributor.author | Perrior, T | - |
dc.contributor.author | McKenzie, G | - |
dc.contributor.author | Blundell, TL | - |
dc.contributor.author | Hyvönen, M | - |
dc.contributor.author | Skidmore, J | - |
dc.contributor.author | Venkitaraman, AR | - |
dc.contributor.author | Abell, C | - |
dc.date.accessioned | 2022-11-03T12:37:18Z | - |
dc.date.available | 2022-11-03T12:37:18Z | - |
dc.date.issued | 2021-03-03 | - |
dc.identifier.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. | en_US |
dc.identifier.issn | 2451-9456 | - |
dc.identifier.uri | https://bura.brunel.ac.uk/handle/2438/25425 | - |
dc.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) | en_US |
dc.description.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. | en_US |
dc.description.sponsorship | Wellcome Trust Translational Award ( 080083/Z/06/Z ); Seeding Drug Discovery Award ( 091058/Z/09/Z ); Medical Research Council (MRC) Program grants MC_UU_12022/1 and MC_UU_12022/8; Astex Pharmaceuticals. | en_US |
dc.format.extent | 835 - 847 (+ e1 - e5) | - |
dc.format.medium | Print-Electronic | - |
dc.language | English | - |
dc.language.iso | en_US | en_US |
dc.publisher | Elsevier Ltd. | en_US |
dc.rights | 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/). | - |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | - |
dc.subject | RAD51 | en_US |
dc.subject | homologous recombination | en_US |
dc.subject | BRCA2 | en_US |
dc.subject | DNA repair | en_US |
dc.subject | structure-guided drug discovery | en_US |
dc.subject | protein-protein interaction inhibition | en_US |
dc.subject | RAD51 inhibitor | en_US |
dc.subject | radiosensitizer | en_US |
dc.subject | cancer therapy | en_US |
dc.title | A small-molecule inhibitor of the BRCA2-RAD51 interaction modulates RAD51 assembly and potentiates DNA damage-induced cell death | en_US |
dc.type | Article | en_US |
dc.identifier.doi | https://doi.org/10.1016/j.chembiol.2021.02.006 | - |
dc.relation.isPartOf | Cell Chemical Biology | - |
pubs.issue | 6 | - |
pubs.publication-status | Published | - |
pubs.volume | 28 | - |
dc.identifier.eissn | 2451-9448 | - |
dc.rights.holder | The Authors | - |
Appears in Collections: | Dept of Life Sciences Research Papers |
Files in This Item:
File | Description | Size | Format | |
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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 |
This item is licensed under a Creative Commons License