title: USP22, an hSAGA subunit and potential cancer stem cell marker, reverses the polycomb-catalyzed ubiquitylation of histone H2A.
abstract: Initial studies of the mammalian hSAGA transcriptional coactivator complex identified the acetyltransferase hGCN5/PCAF as the only known enzymatic subunit. Recently we demonstrated that the ubiquitin hydrolase USP22 comprises a second enzymatic subunit of hSAGA, and that is required for activator-driven transcription. USP22 is expressed with polycomb ubiquitin ligases in an 11 gene signature that defines therapy-resistant tumors. At the biochemical level, these Polycomb proteins function as global transcriptional repressors by catalyzing the ubiquitylation of histone H2A. In yeast, the USP22 homolog functions as a transcriptional coactivator by removing ubiquitin from a distinct core histones, H2B. Given that USP22 is expressed in cancer as part of an 11 gene signature that includes transcriptional repressors which ubiquitylate H2A, it seemed possible that USP22 might activate transcription in part via the deubiquitylation of this same substrate. As reported here, biochemical analysis of the substrate specificity of USP22 reveals that it deubiquitylates histone H2A in addition to H2B. This finding supports a model in which the H2A ubiquitin hydrolase USP22 is coordinately expressed with Polycomb H2A ubiquitin ligases in order that the transcription of certain critical transforming genes be maintained in the face of the global repression mediated by Polycomb.
authors.affiliation: The Department of Cancer Biology, The Kimmel Cancer Center, Thomas Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Xiao-yong
authors.initials: XY
authors.lastname: Zhang
authors.forename: Harla K
authors.initials: HK
authors.lastname: Pfeiffer
authors.forename: Alan W
authors.initials: AW
authors.lastname: Thorne
authors.forename: Steven B
authors.initials: SB
authors.lastname: McMahon
mesh_terms: D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000235:genetics*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism*; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins / Q000378:metabolism; D013869:Thiolester Hydrolases / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase; D054875:Ubiquitination
chemical_list: D006657:Histones; D046912:Multiprotein Complexes; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D013869:Thiolester Hydrolases; D043222:Ubiquitin Thiolesterase; C527170:Usp22 protein, human