Ubiquitin-specific Peptidase 42 (USP42) Functions to Deubiquitylate Histones and Regulate Transcriptional Activity

Background: Ubiquitin modification of histones regulates gene expression. Results: USP42 targets histone H2B at promoters, leading to decreased ubiquitylation. This correlates with the regulation of transcription driven by a number of transcription factors. Conclusion: USP42 contributes to the modulation of transcription. Significance: The identification of histone H2B as a target for USP42 extends our understanding of the factors that can regulate gene expression. Ubiquitin-specific peptidase 42 (USP42) is a deubiquitylating enzyme that can target p53 and contribute to the stabilization of p53 in response to stress. We now show that USP42 can also regulate transcription independently of p53. USP42 co-localized with RNA polymerase II (RNA Pol II) in nuclear foci, bound to histone H2B, and deubiquitylated H2B. Depletion of USP42 increased H2B ubiquitylation at a model promoter and decreased both basal and induced transcription from a number of promoters. These results are consistent with a role for USP42 in regulating transcription by deubiquitylating histones.