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PARG 通过去除抑制性聚 ADP-核糖标记对于 Polθ 介导的 DNA 末端连接是必不可少的。

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

机构信息

Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA.

Thomas Jefferson University, Sidney Kimmel Cancer Center, Department of Biochemistry and Molecular Biology, Philadelphia, PA, 19107, USA.

出版信息

Nat Commun. 2024 Jul 11;15(1):5822. doi: 10.1038/s41467-024-50158-7.

DOI:10.1038/s41467-024-50158-7
PMID:38987289
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11236980/
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.

摘要

DNA 聚合酶θ（Polθ）介导的末端连接（TMEJ）修复 DNA 双链断裂，并赋予对遗传毒性剂的抗性。Polθ 如何在分子水平上受到调节以发挥 TMEJ 的作用仍知之甚少。我们发现，Polθ 以 HPF1 非依赖性方式与 PARP1 相互作用并被 PARP1 多聚化。PARP1 通过 PAR 依赖性液-液相分离将 Polθ 招募到 DNA 损伤附近，然而，由于无法结合 DNA，PAR 化的 Polθ 不能进行 TMEJ。PARG 介导的 Polθ 的去 PAR 化使 Polθ 重新激活其 DNA 结合和末端连接活性。与此一致，PARG 对于 TMEJ 是必不可少的，并且 PARG 向 DNA 损伤的时空募集与 TMEJ 的激活以及 PARP1 和 PAR 的耗散相对应。总之，我们展示了 TMEJ 调节的两步时空机制。首先，PARP1 将 Polθ 多聚化，并以失活状态促进其募集到 DNA 损伤部位。随后，PARG 通过去除 Polθ 上的抑制性 PAR 标记来激活 TMEJ。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/677c/11236980/bc47dd4dfc48/41467_2024_50158_Fig7_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/677c/11236980/bc47dd4dfc48/41467_2024_50158_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/677c/11236980/a88f9b63a897/41467_2024_50158_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/677c/11236980/bc47dd4dfc48/41467_2024_50158_Fig7_HTML.jpg

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