[PDF][PDF] USP22 antagonizes p53 transcriptional activation by deubiquitinating Sirt1 to suppress cell apoptosis and is required for mouse embryonic development

Z Lin, H Yang, Q Kong, J Li, SM Lee, B Gao, H Dong… - Molecular cell, 2012 - cell.com
Z Lin, H Yang, Q Kong, J Li, SM Lee, B Gao, H Dong, J Wei, J Song, DD Zhang, D Fang
Molecular cell, 2012cell.com
The NAD-dependent histone deacetylase Sirt1 antagonizes p53 transcriptional activity to
regulate cell-cycle progression and apoptosis. We have identified a ubiquitin-specific
peptidase, USP22, one of the 11 death-from-cancer signature genes that are critical in
controlling cell growth and death, as a positive regulator of Sirt1. USP22 interacts with and
stabilizes Sirt1 by removing polyubiquitin chains conjugated onto Sirt1. The USP22-
mediated stabilization of Sirt1 leads to decreasing levels of p53 acetylation and suppression …
Summary
The NAD-dependent histone deacetylase Sirt1 antagonizes p53 transcriptional activity to regulate cell-cycle progression and apoptosis. We have identified a ubiquitin-specific peptidase, USP22, one of the 11 death-from-cancer signature genes that are critical in controlling cell growth and death, as a positive regulator of Sirt1. USP22 interacts with and stabilizes Sirt1 by removing polyubiquitin chains conjugated onto Sirt1. The USP22-mediated stabilization of Sirt1 leads to decreasing levels of p53 acetylation and suppression of p53-mediated functions. In contrast, depletion of endogenous USP22 by RNA interference destabilizes Sirt1, inhibits Sirt1-mediated deacetylation of p53 and elevates p53-dependent apoptosis. Genetic deletion of the usp22 gene results in Sirt1 instability, elevated p53 transcriptional activity and early embryonic lethality in mice. Our study elucidates a molecular mechanism in suppression of cell apoptosis by stabilizing Sirt1 in response to DNA damage and reveals a critical physiological function of USP22 in mouse embryonic development.
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