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hMOF Acetylation of DBC1/CCAR2 Prevents Binding and Inhibition of SirT1

机译:DBC1 / CCAR2的hMOF乙酰化可防止SirT1的结合和抑制

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The NAD+-dependent deacetylase SirT1 regulates gene silencing and genomic stability in response to nutrient deprivation and DNA damage. An important regulator of SirT1 in mammalian cells is DBC1 (deleted in breast cancer 1; KIAA1967 or CCAR2), which binds to SirT1 and inhibits the deacetylation of substrates. Recent studies have revealed that ATM/ATR-mediated phosphorylation of DBC1 promotes binding to SirT1. Here we show that DBC1 is modified by acetylation on two N-terminal lysine residues (K112 and K215). The MYST family histone acetyltransferase hMOF (human MOF) is responsible for DBC1 acetylation. Acetylation of K112 and K215 inhibits DBC1-SirT1 binding and increases SirT1 deacetylase activity. SirT1 also promotes DBC1 deacetylation, suggesting the presence of a negative-feedback mechanism that stabilizes the SirT1-DBC1 complex and limits SirT1 activity. hMOF binding and acetylation of DBC1 are inhibited after DNA damage in an ATM-dependent fashion, contributing to increased SirT1-DBC1 binding after DNA damage. Furthermore, a DBC1 mutant that mimics the acetylated state fails to promote apoptosis after DNA damage. These results suggest that acetylation of DBC1 inhibits binding to SirT1 and serves as a mechanism that connects DNA damage signaling to SirT1 and cell fate determination.
机译:NAD + 依赖的脱乙酰基酶SirT1调节基因沉默和基因组稳定性,以响应营养缺乏和DNA损伤。在哺乳动物细胞中,SirT1的重要调控因子是DBC1(在 b reast c ancer 1 中被 d 删除; KIAA1967或CCAR2),它与SirT1结合并抑制底物的脱乙酰基作用。最近的研究表明,ATM / ATR介导的DBC1磷酸化促进与SirT1的结合。在这里,我们显示DBC1被两个N端赖氨酸残基(K112和K215)上的乙酰化修饰。 MYST家族的组蛋白乙酰转移酶hMOF(人MOF)负责DBC1的乙酰化。 K112和K215的乙酰化抑制DBC1-SirT1结合并增加SirT1脱乙酰酶活性。 SirT1还促进DBC1脱乙酰化,表明存在负反馈机制,该机制可稳定SirT1-DBC1复合物并限制SirT1活性。 DNA损伤后,hMOF结合和DBC1的乙酰化以ATM依赖性方式受到抑制,从而导致DNA损伤后SirT1-DBC1结合增加。此外,模拟乙酰化状态的DBC1突变体不能促进DNA损伤后的凋亡。这些结果表明,DBC1的乙酰化抑制了与SirT1的结合,并充当了将DNA损伤信号传导与SirT1和细胞命运确定联系起来的机制。

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