HuR regulates telomerase activity through TERC methylation

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  • 作者：Tang Hao, Wang Hu, Cheng Xiaolei, Fan Xiuqin, Yang Fan, Zhang Mengmeng, Chen Yanlian, Tian Yuyang, Liu Cihang, Shao Dongxing, Jiang Bin, Dou Yali, Cong Yusheng, Xing Junyue, Zhang Xiaotian, Yi Xia, Songyang Zhou, Ma Wenbin, Zhao Yong, Wang Xian, Ma Jinbiao, Gorospe Myriam, Ju Zhenyu, Wang Wengong
  • 期刊：Nature Communications
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Telomerase consists of the catalytic protein TERT and the RNA TERC. Mutations in TERC are linked to human diseases, but the underlying mechanisms are poorly understood. Here we report that the RNA-binding protein HuR associates with TERC and promotes the assembly of the TERC/TERT complex by facilitating TERC C106 methylation. Dyskeratosis congenita (DC)-related TERC U100A mutation impair the association of HuR with TERC, thereby reducing C106 methylation. Two other TERC mutations linked to aplastic anemia and autosomal dominant DC, G107U, and GC107/108AG, likewise disrupt methylation at C106. Loss-of-HuR binding and hence lower TERC methylation leads to decreased telomerase activity and telomere shortening. Furthermore, HuR deficiency or mutation of mTERC HuR binding or methylation sites impair the renewal of mouse hematopoietic stem cells, recapitulating the bone marrow failure seen in DC. Collectively, our findings reveal a novel function of HuR, linking HuR to telomerase function and TERC-associated DC.

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