Chromatin Biology Laboratory, Josep Carreras Leukaemia Research Institute (IJC), Ctra de Can Ruti, Camí de les Escoles s/n, 08916 Badalona, Barcelona, Spain.
Chromatin Biology Laboratory, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Av. Gran Via de l'Hospitalet, 199-203, 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
Nucleic Acids Res. 2023 Jul 21;51(13):6754-6769. doi: 10.1093/nar/gkad504.
The Sirtuin family of NAD+-dependent enzymes plays an important role in maintaining genome stability upon stress. Several mammalian Sirtuins have been linked directly or indirectly to the regulation of DNA damage during replication through Homologous recombination (HR). The role of one of them, SIRT1, is intriguing as it seems to have a general regulatory role in the DNA damage response (DDR) that has not yet been addressed. SIRT1-deficient cells show impaired DDR reflected in a decrease in repair capacity, increased genome instability and decreased levels of γH2AX. Here we unveil a close functional antagonism between SIRT1 and the PP4 phosphatase multiprotein complex in the regulation of the DDR. Upon DNA damage, SIRT1 interacts specifically with the catalytical subunit PP4c and promotes its inhibition by deacetylating the WH1 domain of the regulatory subunits PP4R3α/β. This in turn regulates γH2AX and RPA2 phosphorylation, two key events in the signaling of DNA damage and repair by HR. We propose a mechanism whereby during stress, SIRT1 signaling ensures a global control of DNA damage signaling through PP4.
Sirtuin 家族的 NAD+-依赖性酶在应激时维持基因组稳定性方面发挥着重要作用。几种哺乳动物的 Sirtuins 已被直接或间接地与复制过程中通过同源重组（HR）的 DNA 损伤调节联系起来。其中一个 SIRT1 的作用令人着迷，因为它似乎在 DNA 损伤反应（DDR）中具有普遍的调节作用，而这一作用尚未得到解决。SIRT1 缺陷细胞表现出 DDR 受损，表现在修复能力下降、基因组不稳定性增加和 γH2AX 水平降低。在这里，我们揭示了 SIRT1 与 PP4 磷酸酶多蛋白复合物之间在 DDR 调节中的紧密功能拮抗作用。在 DNA 损伤后，SIRT1 特异性地与催化亚基 PP4c 相互作用，并通过去乙酰化调节亚基 PP4R3α/β 的 WH1 结构域来促进其抑制。这反过来又调节 γH2AX 和 RPA2 的磷酸化，这是 HR 介导的 DNA 损伤和修复信号转导的两个关键事件。我们提出了一种机制，即在应激期间，SIRT1 信号通过 PP4 确保对 DNA 损伤信号进行全局控制。
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