Targeting BRCA1 and BRCA2 Deficiencies with G-Quadruplex-Interacting Compounds.

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Zimmer, Jutta 
Tacconi, Eliana MC 
Folio, Cecilia 
Badie, Sophie 
Porru, Manuela 

G-quadruplex (G4)-forming genomic sequences, including telomeres, represent natural replication fork barriers. Stalled replication forks can be stabilized and restarted by homologous recombination (HR), which also repairs DNA double-strand breaks (DSBs) arising at collapsed forks. We have previously shown that HR facilitates telomere replication. Here, we demonstrate that the replication efficiency of guanine-rich (G-rich) telomeric repeats is decreased significantly in cells lacking HR. Treatment with the G4-stabilizing compound pyridostatin (PDS) increases telomere fragility in BRCA2-deficient cells, suggesting that G4 formation drives telomere instability. Remarkably, PDS reduces proliferation of HR-defective cells by inducing DSB accumulation, checkpoint activation, and deregulated G2/M progression and by enhancing the replication defect intrinsic to HR deficiency. PDS toxicity extends to HR-defective cells that have acquired olaparib resistance through loss of 53BP1 or REV7. Altogether, these results highlight the therapeutic potential of G4-stabilizing drugs to selectively eliminate HR-compromised cells and tumors, including those resistant to PARP inhibition.

Aminoquinolines, Animals, Antineoplastic Agents, BRCA1 Protein, BRCA2 Protein, Biomarkers, Tumor, Cell Proliferation, DNA Breaks, Double-Stranded, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, G-Quadruplexes, G2 Phase Cell Cycle Checkpoints, HEK293 Cells, Humans, Intracellular Signaling Peptides and Proteins, Mad2 Proteins, Male, Mice, Nude, Molecular Targeted Therapy, Neoplasms, Picolinic Acids, Poly(ADP-ribose) Polymerase Inhibitors, RNA Interference, Telomere, Time Factors, Transfection, Tumor Burden, Tumor Suppressor p53-Binding Protein 1, Xenograft Model Antitumor Assays
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Mol Cell
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Elsevier BV
Cancer Research Uk (None)
Wellcome Trust (092096/Z/10/Z)
Cancer Research Uk (None)
E.M.C.T. and C.F. contributed equally to this work. We are grateful to Peter Bouwman and Alexandra Duarte (NKI, Amsterdam), Sven Rottenberg (Vetsuisse, University of Bern), Marie-Paule Teulade-Fichou (Curie Institute, Paris), Steve West (CRUK Clare Hall Laboratories), Hyunsook Lee (Seoul National University), and Carmen D’Angelo (Regina Elena Cancer Institute, Italy) for valuable reagents and/or technical suggestions. Research in the S.P.J. lab is funded by Cancer Research UK program grant C6/A11224, the European Research Council, and the European Community Seventh Framework Program grant agreement number HEALTH-F2-2010-259893 (DDResponse). Core infrastructure funding was provided by Cancer Research UK grant C6946/A14492 and Wellcome Trust grant WT092096. S.P.J. receives salary from the University of Cambridge, supplemented by Cancer Research UK. Research in the K.R. lab is supported by Medical Research Council (MC_PC_12001/1), University of Oxford, and Swiss National Science Foundation (31003A_141197). Work in the A.B. lab is supported by Italian Association for Cancer Research (AIRC # #11567). Work in the J.E.S. lab is supported by a central grant to the Laboratory of Molecular Biology, Cambridge from the Medical Research Council (U105178808). J.Z. is supported by a Cancer Research UK D.Phil. Studentship and E.M.C.T. by a Medical Research Council D.Phil. Studentship. Work in the M.T. lab is supported by Cancer Research UK, Medical Research Council, University of Oxford, and EMBO Young Investigator Program