Ubiquitinated Sirtuin 1 (SIRT1) Function Is Modulated during DNA Damage-induced Cell Death and Survival

• Published in: The Journal of biological chemistry 2015-04, Vol.290 (14), p.8904-8912
• Main Authors: Peng, Lirong, Yuan, Zhigang, Li, Yixuan, Ling, Hongbo, Izumi, Victoria, Fang, Bin, Fukasawa, Kenji, Koomen, John, Chen, Jiandong, Seto, Edward
• Format: Article
• Language: English
• Subjects: Base Sequence; Blotting, Western; Cell Biology; Cell Death - physiology; Cell Line; Cell Survival - physiology; Deubiquitylation (Deubiquitination); DNA Damage; DNA Primers; Fluorescent Antibody Technique; Histone Deacetylase (HDAC); Humans; Post-translational Modification (PTM); Proto-Oncogene Proteins c-mdm2 - metabolism; Sirtuin; Sirtuin 1 - metabolism; Sirtuin 1 - physiology; Ubiquitination; Ubiquitylation (Ubiquitination)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.612796

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. Background: Modulation of histone deacetylase function is crucial for DNA damage-induced cell death and survival. The mechanism of histone deacetylase regulation is poorly understood. Results: Ubiquitination and de-ubiquitination influence sirtuin 1 (SIRT1) histone deacetylase function during DNA damage-induced cell responses. Conclusion: Sirtuin function requires DNA damage-induced SIRT1 ubiquitination. Significance: SIRT1 ubiquitination is a crucial mechanism regulating cell death and survival.