USP22 antagonizes p53 transcriptional activation by deubiquitinating Sirt1 to suppress cell apoptosis and is required for mouse embryonic development. Academic Article uri icon

abstract

  • 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.

published proceedings

  • Mol Cell

altmetric score

  • 0.5

author list (cited authors)

  • Lin, Z., Yang, H., Kong, Q., Li, J., Lee, S., Gao, B., ... Fang, D.

citation count

  • 229

complete list of authors

  • Lin, Zhenghong||Yang, Heeyoung||Kong, Qingfei||Li, Jinping||Lee, Sang-Myeong||Gao, Beixue||Dong, Hongxin||Wei, Jianjun||Song, Jianxun||Zhang, Donna D||Fang, Deyu

publication date

  • January 1, 2012 11:11 AM