Structural basis of histone H2A lysine 119 deubiquitination by Polycomb Repressive Deubiquitinase BAP1/ASXL1

• DOI: 10.1101/2023.02.23.529554
• Publication Date: 2023-02-24T03:10:16Z
• Authors: Jonathan F. Thomas; Marco Igor Valenc...; Simone Tamburri; Susan L. Gloor; Samantha Rustichelli; Victoria Godínez-...; Pablo De Ioannes; Rachel Lee; Stephen Abini-Agb...; Kristjan Gretarsson; Jonathan M. Burg; Allison R. Hickman; Lu Sun; Saarang Gopinath; Hailey Taylor; Matthew J. Meiners; Marcus A. Cheek; William Rice; Evgeny Nudler; Chao Lu; Michael-Christoph...; Diego Pasini; Karim-Jean Armache
• Keywords: Deubiquitinating enzyme; Polycomb-group proteins

Abstract The maintenance of gene expression patterns during metazoan development is achieved by the actions Polycomb group (PcG) complexes. An essential modification marking silenced genes monoubiquitination histone H2A lysine 119 (H2AK119Ub) deposited E3 ubiquitin ligase activity non-canonical Repressive Complex 1. Deubiquitinase (PR-DUB) complex cleaves monoubiquitin from to restrict focal H2AK119Ub at target sites and protect active aberrant silencing. BAP1 ASXL1, subunits that form PR-DUB, are among most frequently mutated epigenetic factors in human cancers, underscoring their biological importance. How PR-DUB achieves specificity for regulate silencing unknown, mechanisms mutations ASXL1 found cancer have not been established. Here we determine a cryo-EM structure bound DEUBAD domain with nucleosome. Our structural, biochemical, cellular data reveal molecular interactions histones DNA critical remodeling nucleosome thus establishing H2AK119Ub. These results further provide explanation how >50 can dysregulate deubiquitination, providing new insight into understanding etiology. One Sentence Summary We mechanism nucleosomal deubiquitination BAP1/ASXL1.