USP7 regulates the ncPRC1 Polycomb axis to stimulate genomic H2AK119ub1 deposition uncoupled from H3K27me3

Ayestha Sijm, Yaser Atlasi, Jan A. van der Knaap, Joyce Wolf van der Meer, Gillian E. Chalkley, Karel Bezstarosti, Dick H.W. Dekkers, Wouter A.S. Doff, Zeliha Ozgur, Wilfred F.J. van IJcken, Jeroen A.A. Demmers*, C. Peter Verrijzer

*Corresponding author for this work

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Ubiquitin-specific protease 7 (USP7) has been implicated in cancer progression and neurodevelopment. However, its molecular targets remain poorly characterized. We combined quantitative proteomics, transcriptomics, and epigenomics to define the core USP7 network. Our multi-omics analysis reveals USP7 as a control hub that links genome regulation, tumor suppression, and histone H2A ubiquitylation (H2AK119ub1) by noncanonical Polycomb-repressive complexes (ncPRC1s). USP7 strongly stabilizes ncPRC1.6 and, to a lesser extent, ncPRC1.1. Moreover, USP7 represses expression of AUTS2, which suppresses H2A ubiquitylation by ncPRC1.3/5. Collectively, these USP7 activities promote the genomic deposition of H2AK119ub1 by ncPRC1, especially at transcriptionally repressed loci. Notably, USP7-dependent changes in H2AK119ub1 levels are uncoupled from H3K27me3. Even complete loss of the PRC1 catalytic core and H2AK119ub1 has only a limited effect on H3K27me3. Besides defining the USP7 regulome, our results reveal that H2AK119ub1 dosage is largely disconnected from H3K27me3.
Original languageEnglish
Article numberabq7598
Number of pages18
JournalScience Advances
Issue number44
Publication statusPublished - 04 Nov 2022

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