Landman, N.; Hulsman, D.; Badhai, J.; van Lohuizen, M.

The tumour suppressor gene BAP1 is mutated in more than half of the malignant mesothelioma patients. This catalytic subunit of Polycomb repressive deubiquitinating (PR-DUB) complex, plays an important role in maintaining gene expression levels by deubiquitinating the PRC1-mediated histone H2A lysine 119 mono-ubiquitination (H2AK119ub1). Published studies report varying degrees of importance of H2AK119ub1 in Polycomb-regulated gene expression in different cell types. Recently published data by our own lab suggests a global redistribution of the H2AK119ub1 mark from promoter to intergenic regions upon loss of BAP1. PRC1-mediated mono-ubiquitination is dependent on the E3 ubiquitin ligase function of RNF2 (RING1B). Here, by knocking-out Rnf2, we show that loss of H2AK119ub1 levels leads to a decrease in clonogenic potential of Bap1-deficient mesothelioma cells in vitro and a delay in tumour onset in vivo.