Peng Lirong, Yuan Zhigang, Li Yixuan, Ling Hongbo, Izumi Victoria, Fang Bin, Fukasawa Kenji, Koomen John, Chen Jiandong, Seto Edward
From the Department of Molecular Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida 33612.
From the Department of Molecular Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida 33612
J Biol Chem. 2015 Apr 3;290(14):8904-12. doi: 10.1074/jbc.M114.612796. Epub 2015 Feb 10.
Downstream signaling of physiological and pathological cell responses depends on post-translational modification such as ubiquitination. The mechanisms regulating downstream DNA damage response (DDR) signaling are not completely elucidated. Sirtuin 1 (SIRT1), the founding member of Class III histone deacetylases, regulates multiple steps in DDR and is closely associated with many physiological and pathological processes. However, the role of post-translational modification or ubiquitination of SIRT1 during DDR is unclear. We show that SIRT1 is dynamically and distinctly ubiquitinated in response to DNA damage. SIRT1 was ubiquitinated by the MDM2 E3 ligase in vitro and in vivo. SIRT1 ubiquitination under normal conditions had no effect on its enzymatic activity or rate of degradation; hypo-ubiquitination, however, reduced SIRT1 nuclear localization. Ubiquitination of SIRT1 affected its function in cell death and survival in response to DNA damage. Our results suggest that ubiquitination is required for SIRT1 function during DDR.
生理和病理细胞反应的下游信号传导取决于翻译后修饰，如泛素化。调节下游DNA损伤反应（DDR）信号传导的机制尚未完全阐明。沉默调节蛋白1（SIRT1）是III类组蛋白脱乙酰酶的创始成员，在DDR中调节多个步骤，并与许多生理和病理过程密切相关。然而，DDR期间SIRT1的翻译后修饰或泛素化作用尚不清楚。我们发现，SIRT1在响应DNA损伤时会发生动态且独特的泛素化。SIRT1在体外和体内被MDM2 E3连接酶泛素化。正常条件下SIRT1的泛素化对其酶活性或降解速率没有影响；然而，低泛素化会降低SIRT1的核定位。SIRT1的泛素化影响其在DNA损伤反应中的细胞死亡和存活功能。我们的结果表明，DDR期间SIRT1功能需要泛素化。
