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PHIP/BRWD2 介导的三价核小体相互作用在神经发育障碍和癌症中被破坏。

A trivalent nucleosome interaction by PHIP/BRWD2 is disrupted in neurodevelopmental disorders and cancer.

机构信息

Simpson Querrey Center for Epigenetics, Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.

EpiCypher, Inc., Durham, North Carolina 27709, USA.

出版信息

Genes Dev. 2021 Dec 1;35(23-24):1642-1656. doi: 10.1101/gad.348766.121. Epub 2021 Nov 24.

DOI:10.1101/gad.348766.121
PMID:34819353
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8653789/
Abstract

Mutations in the chromatin regulator cause the human neurodevelopmental disorder Chung-Jansen syndrome, while alterations in expression are linked to cancer. Precisely how PHIP functions in these contexts is not fully understood. Here we demonstrate that PHIP is a chromatin-associated CRL4 ubiquitin ligase substrate receptor and is required for CRL4 recruitment to chromatin. PHIP binds to chromatin through a trivalent reader domain consisting of a H3K4-methyl binding Tudor domain and two bromodomains (BD1 and BD2). Using semisynthetic nucleosomes with defined histone post-translational modifications, we characterize PHIPs BD1 and BD2 as respective readers of H3K14ac and H4K12ac, and identify human disease-associated mutations in each domain and the intervening linker region that likely disrupt chromatin binding. These findings provide new insight into the biological function of this enigmatic chromatin protein and set the stage for the identification of both upstream chromatin modifiers and downstream targets of PHIP in human disease.

摘要

染色质调控因子的突变导致人类神经发育障碍——钟-詹森综合征，而 的表达改变与癌症有关。PHIP 在这些情况下的确切作用尚不完全清楚。在这里，我们证明 PHIP 是一种与染色质相关的 CRL4 泛素连接酶底物受体，是 CRL4 招募到染色质所必需的。PHIP 通过一个由 H3K4-甲基结合结构域和两个溴结构域（BD1 和 BD2）组成的三价阅读器结构域与染色质结合。使用具有定义的组蛋白翻译后修饰的半合成核小体，我们将 PHIP 的 BD1 和 BD2 分别鉴定为 H3K14ac 和 H4K12ac 的相应阅读器，并在每个结构域和介导电离区鉴定出与人类疾病相关的突变，这些突变可能破坏染色质结合。这些发现为这种神秘的染色质蛋白的生物学功能提供了新的见解，并为鉴定 PHIP 在人类疾病中的上游染色质修饰物和下游靶标奠定了基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a6d7/8653789/3e4514fc45f3/1642f08.jpg
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