2. Academic Validation
  3. PARP3 is a promoter of chromosomal rearrangements and limits G4 DNA

PARP3 is a promoter of chromosomal rearrangements and limits G4 DNA

  • Nat Commun. 2017 Apr 27;8:15110. doi: 10.1038/ncomms15110.
Tovah A Day 1,  Jacob V Layer 1,  J Patrick Cleary 1,  Srijoy Guha 1,  Kristen E Stevenson 2,  Trevor Tivey 1,  Sunhee Kim 1,  Anna C Schinzel 3,  Francesca Izzo 1 3,  John Doench 3,  David E Root 3,  William C Hahn 1 3,  Brendan D Price 4,  David M Weinstock 1 3
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
  • 2 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
  • 3 Genetic Perturbation Platform, Broad Institute of MIT and Harvard University, 415 Main Street, Cambridge, Massachusetts 02142, USA.
  • 4 Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
PMID: 28447610 DOI: 10.1038/ncomms15110
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.

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