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

Autor: Vekariya U; Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA., Minakhin L; Thomas Jefferson University, Sidney Kimmel Cancer Center, Department of Biochemistry and Molecular Biology, Philadelphia, PA, 19107, USA., Chandramouly G; Thomas Jefferson University, Sidney Kimmel Cancer Center, Department of Biochemistry and Molecular Biology, Philadelphia, PA, 19107, USA., Tyagi M; Thomas Jefferson University, Sidney Kimmel Cancer Center, Department of Biochemistry and Molecular Biology, Philadelphia, PA, 19107, USA., Kent T; Thomas Jefferson University, Sidney Kimmel Cancer Center, Department of Biochemistry and Molecular Biology, Philadelphia, PA, 19107, USA., Sullivan-Reed K; Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA., Atkins J; Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA., Ralph D; Thomas Jefferson University, Sidney Kimmel Cancer Center, Department of Biochemistry and Molecular Biology, Philadelphia, PA, 19107, USA., Nieborowska-Skorska M; Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA., Kukuyan AM; Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA., Tang HY; Proteomics and Metabolomics Facility, The Wistar Institute, Philadelphia, PA, 19104, USA., Pomerantz RT; Thomas Jefferson University, Sidney Kimmel Cancer Center, Department of Biochemistry and Molecular Biology, Philadelphia, PA, 19107, USA. richard.pomerantz@jefferson.edu., Skorski T; Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA. tskorski@temple.edu.; Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA. tskorski@temple.edu.; Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA, USA. tskorski@temple.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jul 11; Vol. 15 (1), pp. 5822. Date of Electronic Publication: 2024 Jul 11.
DOI: 10.1038/s41467-024-50158-7
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: