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

Jutta Zimmer; Eliana M C Tacconi; Cecilia Folio; Sophie Badie; Manuela Porru; Kerstin Klare; Manuela Tumiati; Enni Markkanen; Swagata Halder; Anderson Ryan; Stephen P Jackson; Kristijan Ramadan; Sergey G Kuznetsov; Annamaria Biroccio; Julian E Sale; Madalena Tarsounas

doi:10.1016/j.molcel.2015.12.004

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

Mol Cell. 2016 Feb 4;61(3):449-460. doi: 10.1016/j.molcel.2015.12.004. Epub 2015 Dec 31.

Authors

Jutta Zimmer¹, Eliana M C Tacconi¹, Cecilia Folio¹, Sophie Badie¹, Manuela Porru², Kerstin Klare¹, Manuela Tumiati³, Enni Markkanen⁴, Swagata Halder⁵, Anderson Ryan⁶, Stephen P Jackson⁷, Kristijan Ramadan⁵, Sergey G Kuznetsov³, Annamaria Biroccio², Julian E Sale⁸, Madalena Tarsounas⁹

Affiliations

¹ 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.
² Area of Translational Research, Regina Elena National Cancer Institute, 00144 Rome, Italy.
³ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, P.O. Box 20, FIN-00014 Helsinki, Finland.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ The Gurdon Institute, CRUK Laboratories, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK; The Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
⁸ Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
⁹ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aminoquinolines / pharmacology*
Animals
Antineoplastic Agents / pharmacology*
BRCA1 Protein / deficiency*
BRCA1 Protein / genetics
BRCA2 Protein / deficiency*
BRCA2 Protein / genetics
Biomarkers, Tumor / deficiency*
Biomarkers, Tumor / genetics
Cell Proliferation / drug effects
DNA Breaks, Double-Stranded
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
G-Quadruplexes / drug effects*
G2 Phase Cell Cycle Checkpoints / drug effects
HEK293 Cells
Humans
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Mad2 Proteins / genetics
Mad2 Proteins / metabolism
Male
Mice, Nude
Molecular Targeted Therapy
Neoplasms / drug therapy*
Neoplasms / genetics
Neoplasms / metabolism
Neoplasms / pathology
Picolinic Acids / pharmacology*
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
RNA Interference
Telomere / drug effects
Telomere / genetics
Telomere / metabolism
Time Factors
Transfection
Tumor Burden / drug effects
Tumor Suppressor p53-Binding Protein 1
Xenograft Model Antitumor Assays

Substances

Aminoquinolines
Antineoplastic Agents
BRCA1 Protein
BRCA1 protein, human
BRCA2 Protein
BRCA2 protein, human
Biomarkers, Tumor
Intracellular Signaling Peptides and Proteins
MAD2L2 protein, human
Mad2 Proteins
Picolinic Acids
Poly(ADP-ribose) Polymerase Inhibitors
TP53BP1 protein, human
Tumor Suppressor p53-Binding Protein 1
pyridostatin

Abstract

Publication types

MeSH terms

Substances

Grants and funding