Cancer-Specific Retargeting of BAF Complexes by a Prion-like Domain

被引：376

作者：

Boulay, Gaylor ^{[1
,2
,5
,7
,8
]}

Sandoval, Gabriel J. ^{[3
,4
,5
]}

Riggi, Nicolo ^{[6
]}

Iyer, Sowmya ^{[1
,2
]}

Buisson, Remi ^{[7
,8
]}

Naigles, Beverly ^{[1
,2
,7
,8
]}

Awad, Mary E. ^{[1
,2
,7
,8
]}

Rengarajan, Shruthi ^{[1
,2
,7
,8
]}

Volorio, Angela ^{[1
,2
,6
,7
,8
]}

McBride, Matthew J. ^{[3
,4
,5
]}

Broye, Liliane C. ^{[6
]}

Zou, Lee ^{[7
,8
]}

Stamenkovic, Ivan ^{[6
]}

Kadoch, Cigall ^{[3
,4
,5
]}

Rivera, Miguel N. ^{[1
,2
,5
,7
,8
]}

机构：

[1] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[2] Harvard Med Sch, Boston, MA 02114 USA

[3] Dana Farber Canc Inst, Boston, MA 02215 USA

[4] Harvard Med Sch, Boston, MA 02215 USA

[5] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

[6] Univ Lausanne, Inst Pathol, Fac Biol & Med, Ctr Hosp Univ Vaudois, CH-1011 Lausanne, Switzerland

[7] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA

[8] Harvard Med Sch, Charlestown, MA 02129 USA

来源：

CELL | 2017年 / 171卷 / 01期

基金：

瑞士国家科学基金会;

关键词：

CELL-FREE FORMATION; ONCOGENIC FUSION; EWINGS-SARCOMA; GENOMIC LANDSCAPE; CHROMATIN; ELEMENTS; BINDING; EWSR1; TRANSCRIPTION; PROGRAM;

D O I：

10.1016/j.cell.2017.07.036

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：163 / +

页数：35

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