BCOR and BCORL1 mutations disrupt PRC1.1 repressive function in leukemia by unlinking the RING-PCGF1 enzymatic core from target genes
BCOR and BCORL1 mutations disrupt PRC1.1 repressive function in leukemia by unlinking the RING-PCGF1 enzymatic core from target genes
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BCOR 和 BCORL1 突变通过断开 RING-PCGF1 酶核心与靶基因的连接来破坏白血病中 PRC1 1 的抑制功能
DOI：
10.1101/2021.03.08.433705
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Luskin M.R
中科院分区：
文献类型：
--
作者：
Schaefer E.J;Wang H.C;Meyer C.A;Cejas P;Gearhart M.D;Adelman E.R;Fares I;Apffel A;Gibson C.J;Schenone M;Murdock H.M;Wang E.S;Gondek L.P;Carroll M.P;Vedula R.S;Winer E.S;Garcia J.S;Stone R.M;Luskin M.R
BCOR及其类似物BCORL1编码多梳抑制复合体1.1(PRC1.1)的亚单位，并在髓系恶性肿瘤中反复突变。我们发现与白血病相关的BCOR/BCORL1突变使PRC1.1环-PCGF酶核心从含有Kdm2b的染色质靶向辅助亚复合体中解链，要么导致完全蛋白质丢失，要么通过表达缺乏PCGF Ub样折叠鉴别器(PUFD)结构域的C末端截断蛋白质。通过将PRC1.1抑制功能与靶基因解偶联，BCOR/BCORL1突变激活了异常的细胞信号程序，赋予获得性治疗耐药性。这项研究为Polycomb抑制功能障碍作为髓系恶性肿瘤的关键致癌驱动因素提供了机制基础，并确定了BCOR突变癌症靶向治疗的潜在策略。
BCORand its paralogBCORL1encode subunits of the Polycomb repressive complex 1.1 (PRC1.1) and are recurrently mutated in myeloid malignancies. We show that leukemia-associatedBCOR/BCORL1mutations unlink the PRC1.1 RING-PCGF enzymatic core from the KDM2B-containing chromatin targeting auxiliary subcomplex, either by causing complete protein loss or expression of a C-terminally truncated protein lacking the PCGF Ub-like fold discriminator (PUFD) domain. By uncoupling PRC1.1 repressive function from target genes,BCOR/BCORL1mutations activate aberrant cell signaling programs that confer acquired resistance to treatment. This study provides a mechanistic basis for Polycomb repressive dysfunction as a key oncogenic driver in myeloid malignancies and identifies a potential strategy for targeted therapy inBCOR-mutated cancer.
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影响因子：
16
作者：
Gao, Zhonghua;Zhang, Jin;Bonasio, Roberto;Strino, Francesco;Sawai, Ayana;Parisi, Fabio;Kluger, Yuval;Reinberg, Danny
通讯作者：
Reinberg, Danny
影响因子：
11.2
作者：
Charles Schmidt;N. Achille;Aravinda Kuntimaddi;Adam M. Boulton;B. Leach;Shubin Zhang;N. Zeleznik-Le;J. Bushweller
通讯作者：
Charles Schmidt;N. Achille;Aravinda Kuntimaddi;Adam M. Boulton;B. Leach;Shubin Zhang;N. Zeleznik-Le;J. Bushweller
影响因子：
14.9
作者：
Altschul, SF;Madden, TL;Lipman, DJ
通讯作者：
Lipman, DJ
影响因子：
11.2
作者：
Traer E;Martinez J;Javidi-Sharifi N;Agarwal A;Dunlap J;English I;Kovacsovics T;Tyner JW;Wong M;Druker BJ
通讯作者：
Druker BJ
影响因子：
20.3
作者：
Traer, Elie;Javidi-Sharifi, Nathalie;Druker, Brian J.
通讯作者：
Druker, Brian J.