Mutations in the PHIP/BRWD2 chromatin regulator cause the human neurodevelopmental disorder Chung-Jansen syndrome, while alterations in PHIP 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.

中文翻译：

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PHIP/BRWD2 的三价核小体相互作用在神经发育障碍和癌症中被破坏

PHIP/BRWD2染色质调节因子的突变导致人类神经发育障碍 Chung-Jansen 综合征，而PHIP的改变表达与癌症有关。PHIP 如何在这些环境中发挥作用尚不完全清楚。在这里，我们证明 PHIP 是染色质相关的 CRL4 泛素连接酶底物受体，是 CRL4 募集到染色质所必需的。PHIP 通过由 H3K4 甲基结合 Tudor 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。使用具有明确组蛋白翻译后修饰的半合成核小体，我们将 PHIP BD1 和 BD2 定性为 H3K14ac 和 H4K12ac 的各自阅读器，并确定每个结构域和可能破坏染色质结合的干预接头区域中的人类疾病相关突变。