title: The ubiquitin hydrolase USP22 contributes to 3'-end processing of JAK-STAT-inducible genes.
abstract: The JAK-STAT (Janus kinase-signal transducer and activator of transcription) signaling pathway drives cellular growth, differentiation, and the immune response. STAT-activated gene expression is both rapid and transient and requires dynamic post-translational modification of the chromatin template. We previously showed that monoubiquitination of histone H2B (ubH2B) is highly dynamic at the STAT1 target gene, interferon regulatory factor 1 (IRF1), suggesting that a deubiquitinase is recruited during gene activation. Here, we report that RNAi-mediated knockdown of the ubiquitin hydrolase, USP22, results in 2-fold higher ubH2B, and 2-fold lower transcriptional elongation at IRF1. We also demonstrate that USP22 depletion diminishes 3'-end cleavage/polyadenylation by 2- to 3-fold. Furthermore, the polyadenylation factor CPSF73 is not effectively recruited, and serine 2 phosphorylation (Ser2P) of the C-terminal domain of RNA polymerase II is also disrupted. The transcriptional and processing defects observed in the USP22-knockdown cells are reversed by transient USP22 overexpression. Together, these results suggest that ubH2B helps recruit polyadenylation factors to STAT1-activated genes. We propose a working model, wherein a cycle of H2B ubiquitination/deubiquitination specifies Ser2P to regulate elongation and 3'-end processing of JAK-STAT-inducible mRNAs. These results further elaborate USP22 function and its role as a putative cancer stem cell marker.
authors: Department of Biology, The University of Virginia, Charlottesville, VA 22903, USA.
authors: Edmond
authors: E
authors: Chipumuro
authors: Melissa A
authors: MA
authors: Henriksen
mesh_terms: D020413:3' Untranslated Regions; D001483:Base Sequence; D016923:Cell Death / Q000235:genetics; D002460:Cell Line; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D039223:Cleavage And Polyadenylation Specificity Factor / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D055785:Gene Knockdown Techniques; D006657:Histones / Q000378:metabolism; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism*; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D026721:RNA 3' End Processing; D012319:RNA Polymerase II / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013869:Thiolester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D043222:Ubiquitin Thiolesterase; D054875:Ubiquitination
chemical_list: D020413:3' Untranslated Regions; D002843:Chromatin; D039223:Cleavage And Polyadenylation Specificity Factor; D017931:DNA Primers; D006657:Histones; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D009687:Nuclear Proteins; C501972:PAF1 protein, human; D012333:RNA, Messenger; D050791:STAT Transcription Factors; D014157:Transcription Factors; D053612:Janus Kinases; D012319:RNA Polymerase II; D013869:Thiolester Hydrolases; D043222:Ubiquitin Thiolesterase; C527170:Usp22 protein, human