Basis of the H2AK119 specificity of the Polycomb repressive deubiquitinase

Weiran Ge, Cong Yu, Jingjing Li, Zhenyu Yu, Xiaorong Li, Yan Zhang, Chao-Pei Liu, Yingfeng Li, Changlin Tian, Xinzheng Zhang, Guohong Li, Bing Zhu () and Rui-Ming Xu ()
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Weiran Ge: Chinese Academy of Sciences
Cong Yu: Chinese Academy of Sciences
Jingjing Li: Chinese Academy of Sciences
Zhenyu Yu: Chinese Academy of Sciences
Xiaorong Li: Chinese Academy of Sciences
Yan Zhang: Chinese Academy of Sciences
Chao-Pei Liu: Chinese Academy of Sciences
Yingfeng Li: Chinese Academy of Sciences
Changlin Tian: University of Science and Technology of China
Xinzheng Zhang: Chinese Academy of Sciences
Guohong Li: Chinese Academy of Sciences
Bing Zhu: Chinese Academy of Sciences
Rui-Ming Xu: Chinese Academy of Sciences

Nature, 2023, vol. 616, issue 7955, 176-182

Abstract: Abstract Repression of gene expression by protein complexes of the Polycomb group is a fundamental mechanism that governs embryonic development and cell-type specification1–3. The Polycomb repressive deubiquitinase (PR-DUB) complex removes the ubiquitin moiety from monoubiquitinated histone H2A K119 (H2AK119ub1) on the nucleosome4, counteracting the ubiquitin E3 ligase activity of Polycomb repressive complex 1 (PRC1)5 to facilitate the correct silencing of genes by Polycomb proteins and safeguard active genes from inadvertent silencing by PRC1 (refs. 6–9). The intricate biological function of PR-DUB requires accurate targeting of H2AK119ub1, but PR-DUB can deubiquitinate monoubiquitinated free histones and peptide substrates indiscriminately; the basis for its exquisite nucleosome-dependent substrate specificity therefore remains unclear. Here we report the cryo-electron microscopy structure of human PR-DUB, composed of BAP1 and ASXL1, in complex with the chromatosome. We find that ASXL1 directs the binding of the positively charged C-terminal extension of BAP1 to nucleosomal DNA and histones H3–H4 near the dyad, an addition to its role in forming the ubiquitin-binding cleft. Furthermore, a conserved loop segment of the catalytic domain of BAP1 is situated near the H2A–H2B acidic patch. This distinct nucleosome-binding mode displaces the C-terminal tail of H2A from the nucleosome surface, and endows PR-DUB with the specificity for H2AK119ub1.

Date: 2023
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DOI: 10.1038/s41586-023-05841-y

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