PARP3 is a promoter of chromosomal rearrangements and limits G4 DNA

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, Brendan D. Price and David M. Weinstock ()
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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
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
Brendan D. Price: Dana-Farber Cancer Institute, Harvard Medical School
David M. Weinstock: Dana-Farber Cancer Institute

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15110

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