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Dual loss of human POLQ and LIG4 abolishes random integration

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  • Shinta Saito

    (Graduate School of Nanobioscience, Yokohama City University)

  • Ryo Maeda

    (Graduate School of Science, Chiba University)

  • Noritaka Adachi

    (Graduate School of Nanobioscience, Yokohama City University
    Advanced Medical Research Center, Yokohama City University)

Abstract

Homologous recombination-mediated gene targeting has greatly contributed to genetic analysis in a wide range of species, but is highly inefficient in human cells because of overwhelmingly frequent random integration events, whose molecular mechanism remains elusive. Here we show that DNA polymerase θ, despite its minor role in chromosomal DNA repair, substantially contributes to random integration, and that cells lacking both DNA polymerase θ and DNA ligase IV, which is essential for non-homologous end joining (NHEJ), exhibit 100% efficiency of spontaneous gene targeting by virtue of undetectable levels of random integration. Thus, DNA polymerase θ-mediated end joining is the sole homology-independent repair route in the absence of NHEJ and, intriguingly, their combined absence reveals rare Alu-Alu recombination events utilizing a stretch of homology. Our findings provide new insights into the mechanics of foreign DNA integration and the role of DNA polymerase θ in human genome maintenance.

Suggested Citation

  • Shinta Saito & Ryo Maeda & Noritaka Adachi, 2017. "Dual loss of human POLQ and LIG4 abolishes random integration," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
  • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms16112
    DOI: 10.1038/ncomms16112
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    Cited by:

    1. Shinta Saito & Noritaka Adachi, 2024. "Characterization and regulation of cell cycle-independent noncanonical gene targeting," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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