TY - JOUR
T1 - SIRT1 sumoylation regulates its deacetylase activity and cellular response to genotoxic stress
AU - Yang, Yonghua
AU - Fu, Wei
AU - Chen, Jiandong
AU - Olashaw, Nancy
AU - Zhang, Xiaohong
AU - Nicosia, Santo V.
AU - Bhalla, Kapil
AU - Bai, Wenlong
N1 - Funding Information:
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).
PY - 2007/11
Y1 - 2007/11
N2 - 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.
AB - 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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U2 - 10.1038/ncb1645
DO - 10.1038/ncb1645
M3 - Article
C2 - 17934453
AN - SCOPUS:35748962613
VL - 9
SP - 1253
EP - 1262
JO - Nature
JF - Nature
SN - 0028-0836
IS - 11
ER -