Repository logo
 

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

Accepted version
Peer-reviewed

Change log

Authors

Scott, Duncan E 
Francis-Newton, Nicola J 
Marsh, May E 
Coyne, Anthony G 
Fischer, Gerhard 

Abstract

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

Keywords

BRCA2, DNA repair, RAD51, RAD51 inhibitor, cancer therapy, homologous recombination, protein-protein interaction inhibition, radiosensitizer, structure-guided drug discovery, BRCA2 Protein, Cell Death, Crystallography, X-Ray, DNA Damage, Humans, Models, Molecular, Molecular Conformation, Protein Binding, Rad51 Recombinase, Small Molecule Libraries, Tumor Cells, Cultured

Journal Title

Cell Chem Biol

Conference Name

Journal ISSN

2451-9456
2451-9448

Volume Title

28

Publisher

Elsevier BV
Sponsorship
MRC (unknown)
MRC (4050551988)
Wellcome Trust (091058/Z/09/Z)
Wellcome Trust (080083/Z/06/Z)
Medical Research Council (MC_UU_12022/1)
MRC (MC_UU_12022/8)
Research grant / gift from Astex Pharmaceuticals
Relationships
Is derived from: