PHD finger protein 1 (PHF1) is a novel reader for histone H4R3 symmetric dimethylation and coordinates with PRMT5-WDR77/CRL4B complex to promote tumorigenesis.
PHD finger protein 1 (PHF1) is a novel reader for histone H4R3 symmetric dimethylation and coordinates with PRMT5-WDR77/CRL4B complex to promote tumorigenesis.
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PHD Finger Protein 1 (PHF1) 是组蛋白 H4R3 对称二甲基化的新型读取器，并与 PRMT5-WDR77/CRL4B 复合物协调促进肿瘤发生
DOI：
10.1093/nar/gky461
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发表时间：
2018-07-27
影响因子：
14.9
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Liu R;Gao J;Yang Y;Qiu R;Zheng Y;Huang W;Zeng Y;Hou Y;Wang S;Leng S;Feng D;Yu W;Sun G;Shi H;Teng X;Wang Y
组蛋白翻译后修饰主要通过与通常包含多个组蛋白结合域的效应蛋白相互作用来调节染色质结构和功能。 PHF1 [植物同源结构域 (PHD) 指蛋白 1] 包含两种组蛋白阅读器模块，一个 Tudor 结构域和两个 PHD 指，是表观遗传调控和基因组维护的重要因素。虽然在描述 Tudor 结构域的功能方面已经取得了重大进展，但两个 PHD 手指的作用尚不清楚。在这里，我们证明 PHF1 的 N 端 PHD 指可识别 PRMT5-WDR77 催化的 H4R3 (H4R3me2s) 对称二甲基化。然而，PHF1 的 C 端 PHD 指并不与修饰的组蛋白结合，而是直接与 DDB1 相互作用，DDB1 是 CUL4B-环 E3 连接酶复合物 (CRL4B) 的主要成分，负责 H2AK119 单泛素化 (H2AK119ub1)。我们证明 PHF1、PRMT5-WDR77 和 CRL4B 相互相互作用并作为一个功能单元进行协作。对 PHF1/PRMT5/CUL4B 靶标的全基因组分析确定了一组基因，包括 E-cadherin 和 FBXW7，这些基因与细胞生长和迁移至关重要。我们证明PHF1在体内和体外促进细胞增殖、侵袭和肿瘤发生，并发现其表达在多种人类癌症中显着上调。我们的数据确定了 H4R3me2s 的新读者，并为组蛋白精氨酸甲基化和泛素化之间的功能相互作用提供了分子基础。结果还表明，PHF1是癌症进展的关键因素，支持将PHF1作为癌症治疗的靶点。
Histone post–translational modifications regulate chromatin structure and function largely through interactions with effector proteins that often contain multiple histone-binding domains. PHF1 [plant homeodomain (PHD) finger protein 1], which contains two kinds of histone reader modules, a Tudor domain and two PHD fingers, is an essential factor for epigenetic regulation and genome maintenance. While significant progress has been made in characterizing the function of the Tudor domain, the roles of the two PHD fingers are poorly defined. Here, we demonstrated that the N-terminal PHD finger of PHF1 recognizes symmetric dimethylation of H4R3 (H4R3me2s) catalyzed by PRMT5–WDR77. However, the C-terminal PHD finger of PHF1, instead of binding to modified histones, directly interacts with DDB1, the main component of the CUL4B-Ring E3 ligase complex (CRL4B), which is responsible for H2AK119 mono-ubiquitination (H2AK119ub1). We showed that PHF1, PRMT5–WDR77, and CRL4B reciprocally interact with one another and collaborate as a functional unit. Genome-wide analysis of PHF1/PRMT5/CUL4B targets identified a cohort of genes including E-cadherin and FBXW7, which are critically involved in cell growth and migration. We demonstrated that PHF1 promotes cell proliferation, invasion, and tumorigenesis in vivo and in vitro and found that its expression is markedly upregulated in a variety of human cancers. Our data identified a new reader for H4R3me2s and provided a molecular basis for the functional interplay between histone arginine methylation and ubiquitination. The results also indicated that PHF1 is a key factor in cancer progression, supporting the pursuit of PHF1 as a target for cancer therapy.
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DOI：
10.1042/bj20120768
发表时间：
2012-09-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Gu Z;Gao S;Zhang F;Wang Z;Ma W;Davis RE;Wang Z
通讯作者：
Wang Z
影响因子：
5.3
作者：
Cao, Ru;Wang, Hengbin;Zhang, Yi
通讯作者：
Zhang, Yi
影响因子：
50.3
作者：
Davis RJ;Welcker M;Clurman BE
通讯作者：
Clurman BE
DOI：
10.1126/science.aad5214
发表时间：
2016-03-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kryukov GV;Wilson FH;Ruth JR;Paulk J;Tsherniak A;Marlow SE;Vazquez F;Weir BA;Fitzgerald ME;Tanaka M;Bielski CM;Scott JM;Dennis C;Cowley GS;Boehm JS;Root DE;Golub TR;Clish CB;Bradner JE;Hahn WC;Garraway LA
通讯作者：
Garraway LA
影响因子：
5.3
作者：
Dacwag, Caroline S.;Bedford, Mark T.;Imbalzano, Anthony N.
通讯作者：
Imbalzano, Anthony N.