Role of H2A deubiquitination in cell cycle progression and Hox gene expression

Protein ubiquitination regulates a broad spectrum of protein substrates in diverse cellular pathways. One target of ubiquitination is histone H2A. Recent identification of H2A ubiquitin ligase has revealed important roles for H2A ubiquitination in gene silencing and X inactivation. It is not known how ubiquitinated H2A is deubiquitinated and what it’s function is. We purified and identified one deubiquitinase for histone H2A, Ubp‐M. Ubp‐M prefers nucleosomes as substrates and specifically deubiquitinates histone H2A but not H2B in vitro and in vivo . Cells with knockdowns of Ubp‐M exhibit slow growth rates, which are due to defects in M phase of the cell cycle. Biochemical studies indicate that deubiquitination of H2A during M phase of the cell cycle is defected in Ubp‐M knockdown cells and that H2A deubiquitination serves as a prerequisite for subsequent H3Ser10 phosphorylation. In addition, we demonstrate that Ubp‐M regulates HoxD10 gene expression using RT‐PCR and ChIP assays. Therefore, our study defines the deubiquitinase for histone H2A and demonstrates that H2A deubiquitination plays a critical role in cell cycle progression and transcriptional regulation.