HuR regulates telomerase activity through TERC methylation

Hao Tang, Hu Wang, Xiaolei Cheng, Xiuqin Fan, Fan Yang, Mengmeng Zhang, Yanlian Chen, Yuyang Tian, Cihang Liu, Dongxing Shao, Bin Jiang, Yali Dou, Yusheng Cong, Junyue Xing, Xiaotian Zhang, Xia Yi, Zhou Songyang, Wenbin Ma, Yong Zhao, Xian Wang, Jinbiao Ma, Myriam Gorospe, Zhenyu Ju () and Wengong Wang ()
Additional contact information
Hao Tang: Peking University Health Science Center
Hu Wang: Jinan University
Xiaolei Cheng: Peking University Health Science Center
Xiuqin Fan: Peking University Health Science Center
Fan Yang: Jinan University
Mengmeng Zhang: Fudan University
Yanlian Chen: Sun Yat-sen University
Yuyang Tian: Sun Yat-sen University
Cihang Liu: Peking University Health Science Center
Dongxing Shao: Peking University Health Science Center
Bin Jiang: Peking University Health Science Center
Yali Dou: University of Michigan
Yusheng Cong: Jinan University
Junyue Xing: Peking University Health Science Center
Xiaotian Zhang: Peking University Health Science Center
Xia Yi: Peking University Health Science Center
Zhou Songyang: Sun Yat-sen University
Wenbin Ma: Sun Yat-sen University
Yong Zhao: Sun Yat-sen University
Xian Wang: Peking University Health Science Center
Jinbiao Ma: Fudan University
Myriam Gorospe: National Institute on Aging, National Institutes of Health
Zhenyu Ju: Jinan University
Wengong Wang: Peking University Health Science Center

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-04617-7

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