AI Article Synopsis
- DNA polymerase theta (Polθ) is a protein involved in repairing DNA double-strand breaks and helps cells resist harmful agents.
- The regulation of Polθ's activity in this repair process, known as TMEJ (Theta-Mediated End Joining), involves a two-step mechanism where PARP1 first attaches a modification (PARylation) to Polθ, bringing it to damage sites but rendering it inactive.
- The enzyme PARG then removes this modification, restoring Polθ's ability to bind DNA and perform the repair, making PARG crucial for the activation of TMEJ in response to DNA damage.
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.
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|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11236980 | PMC |
| http://dx.doi.org/10.1038/s41467-024-50158-7 | DOI Listing |
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