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Deubiquitination of Tip60 by USP7 determines the activity of the p53-dependent apoptotic pathway.

ABSTRACT: Tip60 is an essential acetyltransferase required for acetylation of nucleosomal histones and other nonhistone proteins. Tip60 acetylates the p53 tumor suppressor at lysine 120 (K120), a modification essential for p53-dependent induction of PUMA and apoptosis. It is known that Tip60 is turned over in cells by the ubiquitin-proteasome system. However, the deubiquitinase activity for stabilizing Tip60 is unknown. Here we show that USP7 interacts with and deubiquitinates Tip60 both in vitro and in vivo. USP7 deubiquitinase activity is required for the stabilization of Tip60 in order to operate an effective p53-dependent apoptotic pathway in response to genotoxic stress. Inhibiting USP7 with the small-molecule inhibitor P22077 attenuates the p53-dependent apoptotic pathway by destabilizing Tip60. P22077, however, is still cytotoxic, and this is partly due to destabilization of Tip60.

SUBMITTER: Dar A

PROVIDER: S-EPMC3753911 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Deubiquitination of Tip60 by USP7 determines the activity of the p53-dependent apoptotic pathway.

Dar Ashraf A Shibata Etsuko E Dutta Anindya A

Molecular and cellular biology 20130617 16

Tip60 is an essential acetyltransferase required for acetylation of nucleosomal histones and other nonhistone proteins. Tip60 acetylates the p53 tumor suppressor at lysine 120 (K120), a modification essential for p53-dependent induction of PUMA and apoptosis. It is known that Tip60 is turned over in cells by the ubiquitin-proteasome system. However, the deubiquitinase activity for stabilizing Tip60 is unknown. Here we show that USP7 interacts with and deubiquitinates Tip60 both in vitro and in v ...[more]

PMID: 23775119

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Correction: USP7 attenuates endoplasmic reticulum stress-induced apoptotic cell death through deubiquitination and stabilization of FBXO7.

Project description:[This corrects the article DOI: 10.1371/journal.pone.0290371.].

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YG001: A Usp7-Tip60 pathway regulates early adipogenesis

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RNF8 promotes efficient DSB repair by inhibiting the pro-apoptotic activity of p53 through regulating the function of Tip60.

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Phosphorylation of Tip60 by GSK-3 determines the induction of PUMA and apoptosis by p53.

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