Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, Army Medical University, Chongqing, China.
Int J Biol Sci. 2022 Mar 27;18(7):2655-2669. doi: 10.7150/ijbs.68587. eCollection 2022.
SIRT1 (silent mating type information regulation 2 homolog 1), a class III histone deacetylase, is known to participate in multiple steps of the DNA damage response (DDR) by deacetylating several key DDR proteins. At present, the mechanisms regulating SIRT1 protein stability upon DNA damage have yet to be fully elucidated. In this study, we reveal that, under severe DNA damage, SIRT1 undergoes two forms of post-translational modifications (PTMs): (i) increased polyubiquitination and proteasomal degradation mediated by TRIM28 (tripartite motif-containing protein 28), a RING-domain E3 ligase; and (ii) cleavage at C-terminal mediated by caspases. Importantly, there is reciprocal effects between these forms of PTMs: while suppression of proteasome reduces caspases-mediated cleavage, the cleaved SIRT1 has enhanced interaction with TRIM28, thus facilitating the ubiquitination and proteasomal degradation of SIRT1. Functionally, SIRT1 works as an anti-apoptotic protein in DDR, and the above-mentioned PTMs of SIRT1 subsequently enhances cell death induced by DNA damage agents. Thus, our study has uncovered a pivotal role of SIRT1 post-translational regulation in determining cell fate in DDR.
SIRT1（沉默交配信息调节 2 同源物 1）是一种 III 类组蛋白去乙酰化酶，已知通过去乙酰化几种关键的 DDR 蛋白参与 DNA 损伤反应 (DDR) 的多个步骤。目前，调节 DNA 损伤后 SIRT1 蛋白稳定性的机制尚未完全阐明。在这项研究中，我们揭示了在严重的 DNA 损伤下，SIRT1 经历两种形式的翻译后修饰 (PTM)：（i）由 TRIM28（三肽基结构域蛋白 28）介导的多聚泛素化和蛋白酶体降解增加，TRIM28 是一种 RING 结构域 E3 连接酶；（ii）由半胱天冬酶介导的 C 端切割。重要的是，这些 PTM 形式之间存在相互作用：虽然抑制蛋白酶体可减少半胱天冬酶介导的切割，但切割的 SIRT1 与 TRIM28 的相互作用增强，从而促进 SIRT1 的泛素化和蛋白酶体降解。功能上，SIRT1 在 DDR 中作为一种抗细胞凋亡蛋白，SIRT1 的上述翻译后修饰随后增强了 DNA 损伤剂诱导的细胞死亡。因此，我们的研究揭示了 SIRT1 翻译后调节在决定 DDR 中细胞命运方面的关键作用。
