title: USP22 antagonizes p53 transcriptional activation by deubiquitinating Sirt1 to suppress cell apoptosis and is required for mouse embryonic development.
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.
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Lin
authors.forename: Heeyoung
authors.initials: H
authors.lastname: Yang
authors.forename: Qingfei
authors.initials: Q
authors.lastname: Kong
authors.forename: Jinping
authors.initials: J
authors.lastname: Li
authors.forename: Sang-Myeong
authors.initials: SM
authors.lastname: Lee
authors.forename: Beixue
authors.initials: B
authors.lastname: Gao
authors.forename: Hongxin
authors.initials: H
authors.lastname: Dong
authors.forename: Jianjun
authors.initials: J
authors.lastname: Wei
authors.forename: Jianxun
authors.initials: J
authors.lastname: Song
authors.forename: Donna D
authors.initials: DD
authors.lastname: Zhang
authors.forename: Deyu
authors.initials: D
authors.lastname: Fang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D004249:DNA Damage; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology*; D010450:Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004795:Enzyme Stability; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011247:Pregnancy; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases; D054875:Ubiquitination
chemical_list: D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D010450:Endopeptidases; D064570:Ubiquitin-Specific Proteases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1