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PARG is essential for Polθ-mediated DNA end-joining by removing repressive poly-ADP-ribose marks

Author

Listed:
  • Umeshkumar Vekariya

    (Temple University)

  • Leonid Minakhin

    (Department of Biochemistry and Molecular Biology)

  • Gurushankar Chandramouly

    (Department of Biochemistry and Molecular Biology)

  • Mrityunjay Tyagi

    (Department of Biochemistry and Molecular Biology)

  • Tatiana Kent

    (Department of Biochemistry and Molecular Biology)

  • Katherine Sullivan-Reed

    (Temple University)

  • Jessica Atkins

    (Temple University)

  • Douglas Ralph

    (Department of Biochemistry and Molecular Biology)

  • Margaret Nieborowska-Skorska

    (Temple University)

  • Anna-Mariya Kukuyan

    (Temple University)

  • Hsin-Yao Tang

    (The Wistar Institute)

  • Richard T. Pomerantz

    (Department of Biochemistry and Molecular Biology)

  • Tomasz Skorski

    (Temple University
    Temple University
    Fox Chase Cancer Center)

Abstract

DNA polymerase theta (Polθ)-mediated end-joining (TMEJ) repairs DNA double-strand breaks and confers resistance to genotoxic agents. How Polθ is regulated at the molecular level to exert TMEJ remains poorly characterized. We find that Polθ interacts with and is PARylated by PARP1 in a HPF1-independent manner. PARP1 recruits Polθ to the vicinity of DNA damage via PARylation dependent liquid demixing, however, PARylated Polθ cannot perform TMEJ due to its inability to bind DNA. PARG-mediated de-PARylation of Polθ reactivates its DNA binding and end-joining activities. Consistent with this, PARG is essential for TMEJ and the temporal recruitment of PARG to DNA damage corresponds with TMEJ activation and dissipation of PARP1 and PAR. In conclusion, we show a two-step spatiotemporal mechanism of TMEJ regulation. First, PARP1 PARylates Polθ and facilitates its recruitment to DNA damage sites in an inactivated state. PARG subsequently activates TMEJ by removing repressive PAR marks on Polθ.

Suggested Citation

  • Umeshkumar Vekariya & Leonid Minakhin & Gurushankar Chandramouly & Mrityunjay Tyagi & Tatiana Kent & Katherine Sullivan-Reed & Jessica Atkins & Douglas Ralph & Margaret Nieborowska-Skorska & Anna-Mari, 2024. "PARG is essential for Polθ-mediated DNA end-joining by removing repressive poly-ADP-ribose marks," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50158-7
    DOI: 10.1038/s41467-024-50158-7
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