Document Type

Article

Publication Date

7-11-2024

Comments

This article is the author's final published version in Nature Communications, Volume 15, 2024, Article number 5822.

The published version is available at https://doi.org/10.1038/s41467-024-50158-7. Copyright © The Author(s) 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.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

Additional Files
Supplementary Information.pdf (1367 kB)
Supplementary Information
Peer Review File.pdf (515 kB)
Peer Review File
Description of Additional Supplementary Files.pdf (82 kB)
Description of Additional Supplementary Files
Supplementary Data 1.xlsx (13 kB)
Supplementary Data 1
Reporting Summary.pdf (73 kB)
Reporting Summary

PubMed ID

38987289

Language

English

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