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

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

Author information

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.

PMID:
26748828
PMCID:
PMC4747901
DOI:
10.1016/j.molcel.2015.12.004
[Indexed for MEDLINE]
Free PMC Article

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