PARG is essential for Polθ-mediated DNA end-joining by removing repressive poly-ADP-ribose marks
Year: 2024
Type: article
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.
Source: Nature Communications
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,790
Awards: G1980002778, Targeting DNA repair to eradicate TKi-refractory/resistant CML and Ph+ALL, G2577297058, G3771709565, G4794054878, G5739139436, G6345179729, Mechanisms of RNA-DNA repair, PolQ as a novel therapeutic target in AML, G7006446046, G7362706921, MPN-inducing mutations as biomarkers of synthetic lethality, Advancing Cancer Research through Comprehensive Proteomics and Metabolomics Analyses, Divergent Functions of ERK Substrate Binding Domains in Pathogenesis of Myeloproliferative Neoplasms, Consolidated Basic Cancer Research Program, Novel Mechanisms and Regulation of Mammalian Double-Strand Break Repair
OpenAlex ID: W4400570848