2. Academic Validation
  3. PARG is essential for Polθ-mediated DNA end-joining by removing repressive poly-ADP-ribose marks

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

  • Nat Commun. 2024 Jul 11;15(1):5822. doi: 10.1038/s41467-024-50158-7.
Umeshkumar Vekariya # 1,  Leonid Minakhin # 2,  Gurushankar Chandramouly 2,  Mrityunjay Tyagi 2,  Tatiana Kent 2,  Katherine Sullivan-Reed 1,  Jessica Atkins 1,  Douglas Ralph 2,  Margaret Nieborowska-Skorska 1,  Anna-Mariya Kukuyan 1,  Hsin-Yao Tang 3,  Richard T Pomerantz 4,  Tomasz Skorski 5 6 7
Affiliations

Affiliations

  • 1 Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA.
  • 2 Thomas Jefferson University, Sidney Kimmel Cancer Center, Department of Biochemistry and Molecular Biology, Philadelphia, PA, 19107, USA.
  • 3 Proteomics and Metabolomics Facility, The Wistar Institute, Philadelphia, PA, 19104, USA.
  • 4 Thomas Jefferson University, Sidney Kimmel Cancer Center, Department of Biochemistry and Molecular Biology, Philadelphia, PA, 19107, USA. richard.pomerantz@jefferson.edu.
  • 5 Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA. tskorski@temple.edu.
  • 6 Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA. tskorski@temple.edu.
  • 7 Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA, USA. tskorski@temple.edu.
  • # Contributed equally.
PMID: 38987289 DOI: 10.1038/s41467-024-50158-7
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.

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