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

DOI: 10.1016/j.chembiol.2021.02.006 DOI Help

Authors: Duncan E. Scott (University of Cambridge) , Nicola J. Francis-Newton (University of Cambridg) , May E. Marsh (University of Cambridge) , Anthony G. Coyne (University of Cambridge) , Gerhard Fischer (University of Cambridge) , Tommaso Moschetti (University of Cambridge) , Andrew R. Bayly (University of Cambridge) , Timothy D. Sharpe (University of Cambridge) , Kalina T. Haas (University of Cambridge) , Lorraine Barber (University of Cambridge) , Chiara R. Valenzano (University of Cambridge) , Rajavel Srinivasan (University of Cambridge; Tianjin University) , David J. Huggins (University of Cambridge) , Miyoung Lee (University of Cambridge) , Amy Emery (University of Cambridge) , Bryn Hardwick (University of Cambridge) , Matthias Ehebauer (University of Cambridge) , Claudio Dagostin (University of Cambridge) , Alessandro Esposito (University of Cambridge) , Luca Pellegrini (University of Cambridge) , Trevor Perrior (University of Cambridge) , Grahame Mckenzie (University of Cambridge) , Tom L. Blundell (University of Cambridge) , Marko Hyvonen (University of Cambridge) , John Skidmore (University of Cambridge) , Ashok R. Venkitaraman (University of Cambridge; National University of Singapore) , Chris Abell (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell Chemical Biology , VOL 66

State: Published (Approved)
Published: March 2021
Diamond Proposal Number(s): 315 , 7141

Open Access Open Access

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.

Journal Keywords: RAD51; homologous recombination. BRCA2. DNA repair. structure-guided drug discovery. protein-protein interaction inhibition. RAD51 inhibitor; radiosensitizer; cancer therapy

Diamond Keywords: Breast Cancer

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: ID14-4 at ESRF

Added On: 10/03/2021 11:18

Documents:
1-s2.0-S2451945621000581-main.pdf

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Cancer Drug Discovery Non-Communicable Diseases Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)