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PARP3 is a promoter of chromosomal rearrangements and limits G4 DNA

Author

Listed:
  • Tovah A. Day

    (Dana-Farber Cancer Institute)

  • Jacob V. Layer

    (Dana-Farber Cancer Institute)

  • J. Patrick Cleary

    (Dana-Farber Cancer Institute)

  • Srijoy Guha

    (Dana-Farber Cancer Institute)

  • Kristen E. Stevenson

    (Dana-Farber Cancer Institute)

  • Trevor Tivey

    (Dana-Farber Cancer Institute)

  • Sunhee Kim

    (Dana-Farber Cancer Institute)

  • Anna C. Schinzel

    (Genetic Perturbation Platform, Broad Institute of MIT and Harvard University)

  • Francesca Izzo

    (Dana-Farber Cancer Institute
    Genetic Perturbation Platform, Broad Institute of MIT and Harvard University)

  • John Doench

    (Genetic Perturbation Platform, Broad Institute of MIT and Harvard University)

  • David E. Root

    (Genetic Perturbation Platform, Broad Institute of MIT and Harvard University)

  • William C. Hahn

    (Dana-Farber Cancer Institute
    Genetic Perturbation Platform, Broad Institute of MIT and Harvard University)

  • Brendan D. Price

    (Dana-Farber Cancer Institute, Harvard Medical School)

  • David M. Weinstock

    (Dana-Farber Cancer Institute
    Genetic Perturbation Platform, Broad Institute of MIT and Harvard University)

Abstract

Chromosomal rearrangements are essential events in the pathogenesis of both malignant and nonmalignant disorders, yet the factors affecting their formation are incompletely understood. Here we develop a zinc-finger nuclease translocation reporter and screen for factors that modulate rearrangements in human cells. We identify UBC9 and RAD50 as suppressors and 53BP1, DDB1 and poly(ADP)ribose polymerase 3 (PARP3) as promoters of chromosomal rearrangements across human cell types. We focus on PARP3 as it is dispensable for murine viability and has druggable catalytic activity. We find that PARP3 regulates G quadruplex (G4) DNA in response to DNA damage, which suppresses repair by nonhomologous end-joining and homologous recombination. Chemical stabilization of G4 DNA in PARP3−/− cells leads to widespread DNA double-strand breaks and synthetic lethality. We propose a model in which PARP3 suppresses G4 DNA and facilitates DNA repair by multiple pathways.

Suggested Citation

  • Tovah A. Day & Jacob V. Layer & J. Patrick Cleary & Srijoy Guha & Kristen E. Stevenson & Trevor Tivey & Sunhee Kim & Anna C. Schinzel & Francesca Izzo & John Doench & David E. Root & William C. Hahn &, 2017. "PARP3 is a promoter of chromosomal rearrangements and limits G4 DNA," Nature Communications, Nature, vol. 8(1), pages 1-15, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15110
    DOI: 10.1038/ncomms15110
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