title: Targeting BRCA1 and BRCA2 Deficiencies with G-Quadruplex-Interacting Compounds.
abstract: 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.
authors.affiliation: Genome Stability and Tumourigenesis Group, CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Jutta
authors.initials: J
authors.lastname: Zimmer
authors.affiliation: Genome Stability and Tumourigenesis Group, CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Eliana M C
authors.initials: EMC
authors.lastname: Tacconi
authors.affiliation: Genome Stability and Tumourigenesis Group, CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Folio
authors.affiliation: Genome Stability and Tumourigenesis Group, CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Badie
authors.affiliation: Area of Translational Research, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Porru
authors.affiliation: Genome Stability and Tumourigenesis Group, CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Klare
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, P.O. Box 20, FIN-00014 Helsinki, Finland.
authors.forename: Manuela
authors.initials: M
authors.lastname: Tumiati
authors.affiliation: Biochemistry and Regulation of DNA Repair Group, CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Enni
authors.initials: E
authors.lastname: Markkanen
authors.affiliation: DNA Damage and Repair Group, CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Swagata
authors.initials: S
authors.lastname: Halder
authors.affiliation: Lung Cancer Translational Science Research Group, CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Anderson
authors.initials: A
authors.lastname: Ryan
authors.affiliation: The Gurdon Institute, CRUK Laboratories, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK; The Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Jackson
authors.affiliation: DNA Damage and Repair Group, CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Kristijan
authors.initials: K
authors.lastname: Ramadan
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, P.O. Box 20, FIN-00014 Helsinki, Finland.
authors.forename: Sergey G
authors.initials: SG
authors.lastname: Kuznetsov
authors.affiliation: Area of Translational Research, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Biroccio
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Julian E
authors.initials: JE
authors.lastname: Sale
authors.affiliation: Genome Stability and Tumourigenesis Group, CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK. Electronic address: madalena.tarsounas@oncology.ox.ac.uk.
authors.forename: Madalena
authors.initials: M
authors.lastname: Tarsounas
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000172:deficiency* / Q000235:genetics; D024682:BRCA2 Protein / Q000172:deficiency* / Q000235:genetics; D014408:Biomarkers, Tumor / Q000172:deficiency* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D054856:G-Quadruplexes / Q000187:drug effects*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D064246:Mad2 Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010848:Picolinic Acids / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D016615:Telomere / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D000071857:Tumor Suppressor p53-Binding Protein 1; D023041:Xenograft Model Antitumor Assays
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; C120552:MAD2L2 protein, human; D064246:Mad2 Proteins; D010848:Picolinic Acids; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; C567962:pyridostatin