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PARP3 is a promoter of chromosomal rearrangements and limits G4 DNA

ABSTRACT: Chromosomal rearrangements are essential events in the pathogenesis of both malignant and nonmalignant disorders, yet the factors affecting their formation are incompletely understood. We developed a zinc finger nuclease translocation reporter (ZITR) and screened for factors that modulate rearrangements in human cells. We identified UBC9 and RAD50 as suppressors and 53BP1, DDB1, and PARP3 as promoters of chromosomal rearrangements across human cell types. We focused on poly(ADP)ribose polymerase 3 (PARP3) as it is dispensable for murine viability and has druggable catalytic activity. We found that PARP3 regulated G quadruplex (G4) DNA in response to DNA damage, which suppressed repair by nonhomologous end-joining and homologous recombination. Chemical stabilization of G4 DNA in PARP3-/- cells led 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE94588 | GEO | 2017/03/01

SECONDARY ACCESSION(S): PRJNA371550

REPOSITORIES: GEO

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Project description:At the organismal level, genome rearrangements are usually deleterious and are often associated with disease. Yet, on an evolutionary scale, they can be beneficial as they provide for rapid genetic diversification. DNA lesions, particularly double-strand breaks (DSBs), are sources of genome instability that can be rectified by various repair processes. Homologous recombination (HR) is highly effective at protecting the genome from DSBs and provides for accurate repair between sister chromatids and homologous chromosomes. Here we show that although random DSBs induced by ionizing radiation in yeast chromosomes are repaired efficiently by HR in G-2 diploid cells, rearrangements are frequent. The chromosome aberrations (ABs) primarily resulted from recombination between Ty retrotransposable elements, the most abundant class of dispersed repetitive DNAs in the genome, while some rearrangements involved other classes of repetitive DNA. Few, if any, of the ABs could be attributed to nonhomologous end-joining (NHEJ). We conclude that only those few DSBs that fall at or near the 3-5% of the genome composed of repetitive DNA elements are effective at generating rearrangements, while other lesions that appear in unique (single copy) sequences are correctly repaired. Thus, by successfully competing with repair that normally occurs between large homologous chromosomal DNAs, the combination of repetitive elements and DSBs provides genome plasticity and a rich source of evolutionary opportunities. Keywords: CGH-array Diploid G-2 yeast cells were exposed to 80 krad of ionizing radiation and plated on rich media to obtain survivor colonies. Genomic DNA from each of 37 survivors (Cy5/red; JW1 to JW13, and A1 to A24) was competitively hybridized to DNA from the parent diploid strain (Cy3/green). Gains of genomic segments in the survivors were detected as continuous regions of positive Log2 Red:Green ratios, while losses were detected as negative Log2 Red:Green ratios.

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PARP3 is a promoter of chromosomal rearrangements and limits G4 DNA

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