Abstract
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.
Highlights
Modulation of histone deacetylase function is crucial for DNA damage-induced cell death and survival
To exclude the possibility of contamination from a Sirtuin 1 (SIRT1)-interacting protein, a stringent guanidinium HCl-urea denaturation method was performed as described previously [27]. In these experiments FLAGSIRT1 was co-expressed with His-tagged Ub, and ubiquitinated (His-tagged) proteins were denatured by guanidinium HCl and pulled down using nickel resin
SIRT1 has well characterized functions in regulating the metabolism and multilayer regulation of DNA damage response (DDR) from damage sensing to cell-fate decision [6]
Summary
Modulation of histone deacetylase function is crucial for DNA damage-induced cell death and survival. Results: Ubiquitination and de-ubiquitination influence sirtuin 1 (SIRT1) histone deacetylase function during DNA damageinduced cell responses. Ubiquitination of SIRT1 affected its function in cell death and survival in response to DNA damage. SIRT1 plays important roles in many normal and abnormal physiological processes [1] such as caloric restriction-related longevity, metabolism, DNA damage response (DDR), aging, and tumorigenesis [2,3,4,5]. SIRT1 plays a role in both cell death and survival by deacetylating several DDR proteins, including p53, Ku70, NBS1, Tip, hMOF, and PARP-1 [3, 7,8,9,10,11,12,13,14]. The current study examines the regulation and functional implications of SIRT1 ubiquitination during DDR
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