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

Umeshkumar Vekariya, Leonid Minakhin, Gurushankar Chandramouly, Mrityunjay Tyagi, Tatiana Kent, Katherine Sullivan-Reed, Jessica Atkins, Douglas Ralph, Margaret Nieborowska-Skorska, Anna-Mariya Kukuyan, Hsin-Yao Tang, Richard T. Pomerantz () and Tomasz Skorski ()
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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

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50158-7

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