Understanding the regulatory mechanisms of Ubp-M and H2A deubiquitination in chromatin and cellular functions

Posttranslational modifications of histones regulate important chromatin and cellular functions. Among them, ubiquitination of histone H2A is correlated to transcriptional repression, such as HOX gene silencing and X chromosome inactiviation. Little was known about the removal of ubiquitin from histones, the enzyme(s) involved and its function in chromatin dynamics. We have identified the protein Ubp-M (USP16) to be the H2A- and nucleosome-specific deubiquitinase. We also demonstrated that Ubp-M-mediated H2A deubiquitination is involved in cell cycle progression to M-phase, HOX gene expression, and posterior development in Xenopus laevis. Furthermore, we have also purified USP12 and USP46 which contain an Ubp-M independent deubiquitinase activity for both uH2A and uH2B. USP12 and USP46 each form a complex with the WD40 repeat-containing protein WDR48, which is required for the deubiquitinase activity. USP12 and USP46 regulate HOX gene expression and gastrulation during Xenopus laevis development. These studies will contribute to the understanding of the regulatory mechanisms of H2A and H2B ubiquitination and deubiquitination, and their biological functions.