当前位置: X-MOL 学术Nat. Cancer › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Dual ARID1A/ARID1B loss leads to rapid carcinogenesis and disruptive redistribution of BAF complexes
Nature Cancer ( IF 22.7 ) Pub Date : 2020-09-07 , DOI: 10.1038/s43018-020-00109-0
Zixi Wang 1 , Kenian Chen 2 , Yuemeng Jia 1 , Jen-Chieh Chuang 1 , Xuxu Sun 1 , Yu-Hsuan Lin 1 , Cemre Celen 1 , Lin Li 1 , Fang Huang 1 , Xin Liu 1 , Diego H Castrillon 3 , Tao Wang 2 , Hao Zhu 1
Affiliation  

SWI/SNF chromatin remodelers play critical roles in development and cancer. The causal links between SWI/SNF complex disassembly and carcinogenesis are obscured by redundancy between paralogous components. Canonical BAF (cBAF)-specific paralogs ARID1A and ARID1B are synthetic lethal in some contexts, but simultaneous mutations in both ARID1s are prevalent in cancer. To understand if and how cBAF abrogation causes cancer, we examined the physiological and biochemical consequences of ARID1A/ARID1B loss. In double-knockout liver and skin, aggressive carcinogenesis followed dedifferentiation and hyperproliferation. In double-mutant endometrial cancer, add-back of either induced senescence. Biochemically, residual cBAF subcomplexes resulting from loss of ARID1 scaffolding were unexpectedly found to disrupt a polybromo-containing BAF (pBAF) function. Of 69 mutations in the conserved scaffolding domains of ARID1 proteins observed in human cancer, 37 caused complex disassembly, partially explaining their mutation spectra. ARID1-less, cBAF-less states promote carcinogenesis across tissues, and suggest caution against paralog-directed therapies for ARID1-mutant cancer.



中文翻译:

双重 ARID1A/ARID1B 丢失导致快速致癌和 BAF 复合物的破坏性重新分布

SWI/SNF 染色质重塑剂在发育和癌症中发挥关键作用。SWI/SNF 复合体分解与致癌作用之间的因果关系被旁系同源成分之间的冗余所掩盖。典型 BAF (cBAF) 特异性旁系同源物 ARID1A 和 ARID1B 在某些情况下是合成致死的,但两种 ARID1 的同时突变在癌症中很普遍。为了了解 cBAF 废除是否以及如何导致癌症,我们检查了 ARID1A/ARID1B 缺失的生理和生化后果。在双基因敲除的肝脏和皮肤中,侵袭性致癌发生在去分化和过度增殖之后。在双突变子宫内膜癌中,添加任一诱导衰老。在生化方面,意外地发现由于 ARID1 支架缺失而导致的残留 cBAF 亚复合物会破坏含多溴的 BAF (pBAF) 功能。在人类癌症中观察到的 ARID1 蛋白的保守支架结构域中的 69 个突变中,有 37 个引起了复杂的分解,部分解释了它们的突变谱。无 ARID1、无 cBAF 的状态促进了跨组织的致癌作用,并建议谨慎对待 ARID1 突变癌症的旁系同源定向疗法。

更新日期:2020-09-08
down
wechat
bug