Tumour-associated missense mutations in the dMi-2 ATPase alters nucleosome remodelling properties in a mutation-specific manner.
Tumour-associated missense mutations in the dMi-2 ATPase alters nucleosome remodelling properties in a mutation-specific manner.
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DOI：
10.1038/s41467-018-04503-2
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发表时间：
2018-05-29
影响因子：
16.6
通讯作者：
Brehm A
中科院分区：
文献类型：
--
作者：
Kovač K;Sauer A;Mačinković I;Awe S;Finkernagel F;Hoffmeister H;Fuchs A;Müller R;Rathke C;Längst G;Brehm A
依赖atp的染色质重塑蛋白在超过20%的人类癌症中发生突变。这些突变对酶功能的影响尚不清楚。在这里，我们描述了子宫内膜癌中发现的CHD4突变对dMi-2重塑特性的影响，dMi-2是高度保守的CHD4在果蝇中的同源物。来自不同患者的突变在核小体结合、atp酶活性和核小体重塑方面有着惊人的不同缺陷。出乎意料的是，我们发现了降低和增加酶活性的突变。我们的结果定义了色域和一个新的调控区域是核小体重塑所必需的。果蝇的遗传实验表明，癌症来源的dMi-2突变体的表达错误地调节上皮翼结构的分化，并产生与其核小体重塑特性相关的表型。我们的结果有助于在机制水平上定义CHD4在癌症中的缺陷，并为旨在恢复其活性的分子方法的发展提供基础。依赖atp的染色质重塑子经常在人类癌症中发现突变。在这里，作者描述了果蝇Chd4同源基因dMi-2的癌症相关突变体的核小体重塑特性。
ATP-dependent chromatin remodellers are mutated in more than 20% of human cancers. The consequences of these mutations on enzyme function are poorly understood. Here, we characterise the effects of CHD4 mutations identified in endometrial carcinoma on the remodelling properties of dMi-2, the highly conserved Drosophila homologue of CHD4. Mutations from different patients have surprisingly diverse defects on nucleosome binding, ATPase activity and nucleosome remodelling. Unexpectedly, we identify both mutations that decrease and increase the enzyme activity. Our results define the chromodomains and a novel regulatory region as essential for nucleosome remodelling. Genetic experiments in Drosophila demonstrate that expression of cancer-derived dMi-2 mutants misregulates differentiation of epithelial wing structures and produces phenotypes that correlate with their nucleosome remodelling properties. Our results help to define the defects of CHD4 in cancer at the mechanistic level and provide the basis for the development of molecular approaches aimed at restoring their activity. ATP-dependent chromatin remodelers are often found mutated in human cancers. Here, the authors characterize the nucleosome remodelling properties of cancer-associated mutants of the Drosophila Chd4 homolog dMi-2.
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影响因子：
3.5
作者：
Längst G;Manelyte L
通讯作者：
Manelyte L
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
16
作者：
Corona, DFV;Längst, G;Becker, PB
通讯作者：
Becker, PB
影响因子：
4.5
作者：
Fasulo B;Deuring R;Murawska M;Gause M;Dorighi KM;Schaaf CA;Dorsett D;Brehm A;Tamkun JW
通讯作者：
Tamkun JW
影响因子：
30.8
作者：
Le Gallo, Matthieu;O'Hara, Andrea J.;Rudd, Meghan L.;Urick, Mary Ellen;Hansen, Nancy F.;O'Neil, Nigel J.;Price, Jessica C.;Zhang, Suiyuan;England, Bryant M.;Godwin, Andrew K.;Sgroi, Dennis C.;Hieter, Philip;Mullikin, James C.;Merino, Maria J.;Bell, Daphne W.
通讯作者：
Bell, Daphne W.