Cancer-Specific Retargeting of BAF Complexes by a Prion-like Domain.
Cancer-Specific Retargeting of BAF Complexes by a Prion-like Domain.
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DOI：
10.1016/j.cell.2017.07.036
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发表时间：
2017-09-21
期刊：
影响因子：
64.5
通讯作者：
Rivera MN
中科院分区：
文献类型：
--
作者：
Boulay G;Sandoval GJ;Riggi N;Iyer S;Buisson R;Naigles B;Awad ME;Rengarajan S;Volorio A;McBride MJ;Broye LC;Zou L;Stamenkovic I;Kadoch C;Rivera MN
转录调控因子的改变可以在癌症中协调致癌基因的表达程序。在这里，我们发现BRG1/BRM相关因子(BAF)染色质重塑复合体在超过20%的人类肿瘤中发生突变，它与EWSR1相互作用，EWSR1是带有PrLD的蛋白质家族的成员，PrLD是癌基因与转录因子融合的频繁伙伴。在尤文肉瘤中，我们发现BAF复合体被EWS-FLI1融合蛋白招募到肿瘤特异性增强剂，并有助于靶基因的激活。与野生型FLI1相比，这一过程是EWS-FLI1的新形态特性，并且依赖于EWSR1蛋白样域的相变所必需的酪氨酸残基。此外，EWSR1和FLI1的短片段融合足以重现BAF复合体的重定向和EWS-FLI1的活性。因此，我们的研究表明，Pron样结构域的物理性质可以重定向关键的染色质调节复合体，以建立和维持致癌基因表达程序。癌基因融合蛋白中类病毒结构域的相变特性对于重定向BAF染色质重塑复合体和激活增强子至关重要，从而驱动促进尤文肉瘤的转录程序。
Alterations in transcriptional regulators can orchestrate oncogenic gene expression programs in cancer. Here, we show that the BRG1/BRM-associated factor (BAF) chromatin remodeling complex, which is mutated in over 20% of human tumors, interacts with EWSR1, a member of a family of proteins with prion-like domains (PrLD) that are frequent partners in oncogenic fusions with transcription factors. In Ewing sarcoma, we find that the BAF complex is recruited by the EWS-FLI1 fusion protein to tumor-specific enhancers and contributes to target gene activation. This process is a neomorphic property of EWS-FLI1 compared to wild-type FLI1 and depends on tyrosine residues that are necessary for phase transitions of the EWSR1 prion-like domain. Furthermore, fusion of short fragments of EWSR1 to FLI1 is sufficient to recapitulate BAF complex retargeting and EWS-FLI1 activities. Our studies thus demonstrate that the physical properties of prion-like domains can retarget critical chromatin regulatory complexes to establish and maintain oncogenic gene expression programs. Phase transition properties of a prion-like domain in an oncogenic fusion protein are critical for retargeting BAF chromatin remodeling complexes and activating enhancers, thereby driving the transcriptional program that promotes Ewing sarcoma.
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哺乳动物SWI/SNF复合物的蛋白质组学和生物信息学分析确定了在人类恶性肿瘤中的广泛作用。
影响因子：
30.8
作者：
Kadoch, Cigall;Hargreaves, Diana C.;Hodges, Courtney;Elias, Laura;Ho, Lena;Ranish, Jeff;Crabtree, Gerald R.
通讯作者：
Crabtree, Gerald R.
影响因子：
--
作者：
Herrero-Martin D;Fourtouna A;Niedan S;Riedmann LT;Schwentner R;Aryee DN
通讯作者：
Aryee DN
致癌EWS-FLI1蛋白在体内GGAA微卫星序列结合了潜在的转录激活函数。
影响因子：
3.7
作者：
Guillon N;Tirode F;Boeva V;Zynovyev A;Barillot E;Delattre O
通讯作者：
Delattre O
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
影响因子：
11.2
作者：
Embree LJ;Azuma M;Hickstein DD
通讯作者：
Hickstein DD