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SIRT1 sumoylation regulates its deacetylase activity and cellular response to genotoxic stress

Nature Cell Biology volume 9, pages 1253–1262 (2007)Cite this article

A Corrigendum to this article was published on 01 December 2007

Abstract

SIRT1 is the closest mammalian homologue of yeast SIR2, an important ageing regulator that prolongs lifespan in response to caloric restriction. Despite its importance, the mechanisms that regulate SIRT1 activity are unclear. Our study identifies a novel post-translational modification of SIRT1, namely sumoylation at Lys 734. In vitro sumoylation of SIRT1 increased its deacetylase activity. Conversely, mutation of SIRT1 at Lys 734 or desumoylation by SENP1, a nuclear desumoylase, reduced its deacetylase activity. Stress-inducing agents promoted the association of SIRT1 with SENP1 and cells depleted of SENP1 (but not of SENP1 and SIRT1) were more resistant to stress-induced apoptosis than control cells. We suggest that stress-inducing agents counteract the anti-apoptotic activity of SIRT1 by recruiting SENP1 to SIRT1, which results in the desumoylation and inactivation of SIRT1 and the consequent acetylation and activation of apoptotic proteins.

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Figure 1: SIRT1 is sumoylated in vivo and in vitro.
Figure 2: Mutation of the sumoylation sites of SIRT1 inhibits its function.
Figure 3: Sumoylation of SIRT1 at Lys 734 increases its intrinsic deacetylase activity.
Figure 4: Desumoylation of SIRT1 by SENP1 reduces its ability to deacetylate p53.
Figure 5: SIRT1 desumoylation by UV radiation and hydrogen peroxide contributes to stress-induced apoptosis.
Figure 6: SENP1 interacts with and desumoylates SIRT1 and promotes stress-induced apoptosis.
Figure 7: p53 and p73 mediate the effect of SIRT1 desumoylation on the cellular response to genotoxic stress.

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Acknowledgements

The authors thank E. T. Yeh at the M. D Anderson Cancer Center for SENP1 and SENP1 siRNA vectors. FACS analyses were performed in the Flow Cytometry core facility at H. Lee Moffitt Cancer Center and Research Institute. The work was supported by the Public Health Service grant CA93666 (W.B) and a DOD Prostate Cancer grant DAMD17-02-1-0140 (W.B).

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Author notes

  1. Yonghua Yang

    Present address: Current address: Medical College of Georgia Cancer Center, 1120 15th Street, CN2101A, Augusta, GA 30912, USA.,

Authors and Affiliations

  1. Departments of Pathology and Cell Biology, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, 33612–4799, Florida, USA

    Yonghua Yang, Wei Fu, Xiaohong Zhang, Santo V. Nicosia & Wenlong Bai

  2. Department of Interdisciplinary Oncology, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, 33612–4799, Florida, USA

    Jiandong Chen, Nancy Olashaw, Xiaohong Zhang, Santo V. Nicosia & Wenlong Bai

  3. Program of Molecular Oncology, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, 33612, Florida, USA

    Jiandong Chen, Nancy Olashaw, Xiaohong Zhang & Wenlong Bai

  4. Program of Experimental Therapeutics, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, 33612, Florida, USA

    Santo V. Nicosia

  5. Medical College of Georgia Cancer Center, 1120 15th Street, CN2101A, GA 30912, Augusta, USA

    Kapil Bhalla

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Contributions

Y.Y. designed (with W.B.) and performed (with W.F.) the included studies. J.C., X.Z. and K.B. contributed scientifically to the revision. The manuscript was written by W.B., edited by N.O. and S.V.N. and read by all authors. The senior author (W.B.) designed the project, helped with the analyses and the organization of the data, and provided the financial support. All authors have discussed the data and had scientific input into the manuscript.

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Correspondence to Wenlong Bai.

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Yang, Y., Fu, W., Chen, J. et al. SIRT1 sumoylation regulates its deacetylase activity and cellular response to genotoxic stress. Nat Cell Biol 9, 1253–1262 (2007). https://doi.org/10.1038/ncb1645

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