Day, Tovah A.Layer, Jacob V.Cleary, J. PatrickGuha, SrijoyStevenson, Kristen E.Tivey, TrevorKim, SunheeSchinzel, Anna C.Izzo, FrancescaDoench, JohnRoot, David E.Hahn, WilliamPrice, BrendanWeinstock, David2017-06-152017Day, T. A., J. V. Layer, J. P. Cleary, S. Guha, K. E. Stevenson, T. Tivey, S. Kim, et al. 2017. “PARP3 is a promoter of chromosomal rearrangements and limits G4 DNA.” Nature Communications 8 (1): 15110. doi:10.1038/ncomms15110. http://dx.doi.org/10.1038/ncomms15110.http://nrs.harvard.edu/urn-3:HUL.InstRepos:33029857Chromosomal 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.en-USJournal Article2017-06-1510.1038/ncomms15110