Hulsman, D. | bioRxiv Science

bioRxiv2024

Loss of RNF2 delays tumour development in BAP1-deficient mesothelioma

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.

cancer biology↗

bioRxiv2020

USP15 deubiquitinase safeguards hematopoiesis and genome integrity in hematopoietic stem cells and leukemia cells

Altering ubiquitination by disruption of individual deubiquitinating enzymes (DUBs) has proven to affect hematopoietic stem cell (HSC) maintenance. However, comprehensive knowledge of DUB function during hematopoiesis in vivo is lacking. To accomplish this goal, we systematically inactivated DUBs in mouse hematopoietic progenitors using in vivo small hairpin RNAs (shRNAs) screens. We found that multiple DUBs may be individually required for hematopoiesis and that the ubiquitin-specific protease 15 (USP15) is particularly important for the maintenance of murine hematopoietic stem and progenitor cells in vitro and in vivo. Consistently, Usp15 knockout mice exhibited a reduced HSC pool. The defect was intrinsic to HSCs, as demonstrated by competitive repopulation assays. Importantly, USP15 is highly expressed in normal human hematopoietic cells and leukemias, and USP15 depletion in murine early progenitors and myeloid leukemia cells impaired in vitro expansion and increased genotoxic stress. Our study underscores the importance of DUBs in preserving normal hematopoiesis and uncovers USP15 as a critical DUB in safeguarding genome integrity in HSC and in leukemia cells.

genetics↗