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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
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
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:
Non-Communicable Diseases
Health & Wellbeing
Cancer
Biochemistry
Chemistry
Structural biology
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)