Back to Search Start Over

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

Authors :
Vekariya, Umeshkumar
Minakhin, Leonid
Chandramouly, Gurushankar
Tyagi, Mrityunjay
Kent, Tatiana
Sullivan-Reed, Katherine
Atkins, Jessica
Ralph, Douglas
Nieborowska-Skorska, Margaret
Kukuyan, Anna-Mariya
Tang, Hsin-Yao
Pomerantz, Richard T.
Skorski, Tomasz
Source :
Nature Communications; 7/10/2024, Vol. 15 Issue 1, p1-18, 18p
Publication Year :
2024

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. Here the authors reveal a two-step spatiotemporal regulation of (Polθ)-mediated end-joining (TMEJ). First, PARP1 PARylates Polθ and facilitates its recruitment to the vicinity of DNA damage sites in an inactivated state. PARG subsequently activates TMEJ by removing repressive PAR marks on Polθ. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
20411723
Volume :
15
Issue :
1
Database :
Complementary Index
Journal :
Nature Communications
Publication Type :
Academic Journal
Accession number :
178402971
Full Text :
https://doi.org/10.1038/s41467-024-50158-7