MassIVE MSV000092839

Partial Public PXD045320

PARG is Essential for Pol-theta-Mediated DNA End-Joining by Removing Repressive Poly-ADP Ribose Marks

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Description

DNA polymerase theta (Pol-theta)-mediated end-joining (TMEJ) repairs DNA double-strand breaks and confers resistance to genotoxic agents. How Pol-theta is regulated at the molecular level to exert TMEJ remains unknown. We find that Pol-theta interacts with and is PARylated by PARP1 in vitro and in cells. PARP1 recruits Pol-theta to the vicinity of DNA damage via PARylation dependent liquid demixing, however, PARylated Pol-theta (PAR-Pol-theta) cannot perform TMEJ due to its inability to bind DNA. PARG-mediated de-PARylation of Pol-theta reactivates its DNA binding and end-joining activities in vitro. Consistent with this, PARG is essential for TMEJ in cells and the temporal recruitment of PARG to DNA damage corresponds with TMEJ activation and dissipation of PARP1 and PAR. These studies support a two-step spatiotemporal mechanism of TMEJ regulation. First, PARP1 PARylates Pol-theta and facilitates its recruitment to DNA damage sites in an inactivated state. PARG subsequently activates TMEJ by removing repressive PAR marks on Pol-theta. [doi:10.25345/C51Z4239H] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: DNA polymerase theta ; PARP1

Contact

Principal Investigators:
(in alphabetical order) 		Tomasz Skorski, Temple University, United States
Submitting User: tangh

Publications

Vekariya U, Minakhin L, Chandramouly G, Tyagi M, Kent T, Sullivan-Reed K, Atkins J, Ralph D, Nieborowska-Skorska M, Kukuyan AM, Tang HY, Pomerantz RT, Skorski T.
PARG is essential for Pol?-mediated DNA end-joining by removing repressive poly-ADP-ribose marks.
Nat Commun. 2024 Jul 11;15(1):5822. Epub 2024 Jul 11.

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