Structural basis of histone H2A lysine 119 deubiquitination by Polycomb repressive deubiquitinase BAP1/ASXL1.

Histone H2A lysine 119 (H2AK119Ub) is monoubiquitinated by Polycomb repressive complex 1 and deubiquitinated by Polycomb repressive deubiquitinase complex (PR-DUB). PR-DUB cleaves H2AK119Ub to restrict focal H2AK119Ub at Polycomb target sites and to protect active genes from aberrant silencing. The PR-DUB subunits (BAP1 and ASXL1) are among the most frequently mutated epigenetic factors in human cancers. How PR-DUB establishes specificity for H2AK119Ub over other nucleosomal ubiquitination sites and how disease-associated mutations of the enzyme affect activity are unclear. Here, we determine a cryo-EM structure of human BAP1 and the ASXL1 DEUBAD in complex with a H2AK119Ub nucleosome. Our structural, biochemical, and cellular data reveal the molecular interactions of BAP1 and ASXL1 with histones and DNA that are critical for restructuring the nucleosome and thus establishing specificity for H2AK119Ub. These results further provide a molecular explanation for how >50 mutations in BAP1 and ASXL1 found in cancer can dysregulate H2AK119Ub deubiquitination, providing insight into understanding cancer etiology.

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

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

Accuracy of 'My Gut Feeling:' Comparing System 1 to System 2 Decision-Making for Acuity Prediction, Disposition and Diagnosis in an Academic Emergency Department.

INTRODUCTION: Current cognitive sciences describe decision-making using the dual-process theory, where a System 1 is intuitive and a System 2 decision is hypothetico-deductive. We aim to compare the performance of these systems in determining patient acuity, disposition and diagnosis. METHODS: Prospective observational study of emergency physicians assessing patients in the emergency department of an academic center. Physicians were provided the patient's chief complaint and vital signs and allowed to observe the patient briefly. They were then asked to predict acuity, final disposition (home, intensive care unit (ICU), non-ICU bed) and diagnosis. A patient was classified as sick by the investigators using previously published objective criteria. RESULTS: We obtained 662 observations from 289 patients. For acuity, the observers had a sensitivity of 73.9% (95% CI [67.7-79.5%]), specificity 83.3% (95% CI [79.5-86.7%]), positive predictive value 70.3% (95% CI [64.1-75.9%]) and negative predictive value 85.7% (95% CI [82.0-88.9%]). For final disposition, the observers made a correct prediction in 80.8% (95% CI [76.1-85.0%]) of the cases. For ICU admission, emergency physicians had a sensitivity of 33.9% (95% CI [22.1-47.4%]) and a specificity of 96.9% (95% CI [94.0-98.7%]). The correct diagnosis was made 54% of the time with the limited data available. CONCLUSION: System 1 decision-making based on limited information had a sensitivity close to 80% for acuity and disposition prediction, but the performance was lower for predicting ICU admission and diagnosis. System 1 decision-making appears insufficient for final decisions in these domains but likely provides a cognitive framework for System 2 decision-making.