Structure-function relationships explain CTCF zinc finger mutation phenotypes in cancer.
Structure-function relationships explain CTCF zinc finger mutation phenotypes in cancer.
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DOI：
10.1007/s00018-021-03946-z
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Rasko JEJ
中科院分区：
文献类型：
--
作者：
Bailey CG;Gupta S;Metierre C;Amarasekera PMS;O'Young P;Kyaw W;Laletin T;Francis H;Semaan C;Sharifi Tabar M;Singh KP;Mullighan CG;Wolkenhauer O;Schmitz U;Rasko JEJ
CCCTC结合因子（CTCF）在转录调控和染色质结构维持中起重要作用。CTCF也是一种在癌症中经常突变的肿瘤抑制因子，然而，突变的结构和功能影响尚未得到研究。我们对发生在关键的ZF内和ZF间残基内的五种癌症特异性CTCF错义锌指（ZF）突变进行了分子和结构表征。CTCF ZF突变的功能表征揭示了CTCF的抗增殖作用的完全（L309 P、R339 W、R377 H）或中间（R339 Q）消除以及增强（G420 D）。DNA结合在选定的网站被破坏和转录调控活动废除。分子对接和分子动力学证实，特异性接触DNA碱基或骨架的残基中的突变表现出DNA结合的丧失。然而，R339 Q和G420 D通过形成新的一级DNA键而稳定，有助于功能获得。我们的数据证实，在细胞生长调节和基因调控活动中观察到CTCF锌指功能丧失、改变和获得的影响。因此，不同的细胞表型的突变CTCF清楚地解释了检查结构-功能关系。在线版本包含补充材料，可通过10.1007/s 00018 -021-03946-z获得。
CCCTC-binding factor (CTCF) plays fundamental roles in transcriptional regulation and chromatin architecture maintenance. CTCF is also a tumour suppressor frequently mutated in cancer, however, the structural and functional impact of mutations have not been examined. We performed molecular and structural characterisation of five cancer-specific CTCF missense zinc finger (ZF) mutations occurring within key intra- and inter-ZF residues. Functional characterisation of CTCF ZF mutations revealed a complete (L309P, R339W, R377H) or intermediate (R339Q) abrogation as well as an enhancement (G420D) of the anti-proliferative effects of CTCF. DNA binding at select sites was disrupted and transcriptional regulatory activities abrogated. Molecular docking and molecular dynamics confirmed that mutations in residues specifically contacting DNA bases or backbone exhibited loss of DNA binding. However, R339Q and G420D were stabilised by the formation of new primary DNA bonds, contributing to gain-of-function. Our data confirm that a spectrum of loss-, change- and gain-of-function impacts on CTCF zinc fingers are observed in cell growth regulation and gene regulatory activities. Hence, diverse cellular phenotypes of mutant CTCF are clearly explained by examining structure–function relationships. The online version contains supplementary material available at 10.1007/s00018-021-03946-z.
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影响因子：
30.8
作者：
Liu Y;Easton J;Shao Y;Maciaszek J;Wang Z;Wilkinson MR;McCastlain K;Edmonson M;Pounds SB;Shi L;Zhou X;Ma X;Sioson E;Li Y;Rusch M;Gupta P;Pei D;Cheng C;Smith MA;Auvil JG;Gerhard DS;Relling MV;Winick NJ;Carroll AJ;Heerema NA;Raetz E;Devidas M;Willman CL;Harvey RC;Carroll WL;Dunsmore KP;Winter SS;Wood BL;Sorrentino BP;Downing JR;Loh ML;Hunger SP;Zhang J;Mullighan CG
通讯作者：
Mullighan CG
影响因子：
64.8
作者：
通讯作者：
--
弥漫性大 B 细胞淋巴瘤中超级增强子相关依赖性的发现和表征。
影响因子：
50.3
作者：
Chapuy B;McKeown MR;Lin CY;Monti S;Roemer MG;Qi J;Rahl PB;Sun HH;Yeda KT;Doench JG;Reichert E;Kung AL;Rodig SJ;Young RA;Shipp MA;Bradner JE
通讯作者：
Bradner JE
影响因子：
64.5
作者：
Hu J;Zhang Y;Zhao L;Frock RL;Du Z;Meyers RM;Meng FL;Schatz DG;Alt FW
通讯作者：
Alt FW
影响因子：
64.5
作者：
Delmore JE;Issa GC;Lemieux ME;Rahl PB;Shi J;Jacobs HM;Kastritis E;Gilpatrick T;Paranal RM;Qi J;Chesi M;Schinzel AC;McKeown MR;Heffernan TP;Vakoc CR;Bergsagel PL;Ghobrial IM;Richardson PG;Young RA;Hahn WC;Anderson KC;Kung AL;Bradner JE;Mitsiades CS
通讯作者：
Mitsiades CS