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.

Details

Title
HuR regulates telomerase activity through TERC methylation
Author
Tang, Hao 1 ; Wang, Hu 2 ; Cheng, Xiaolei 3 ; Fan, Xiuqin 3 ; Yang, Fan 4 ; Zhang, Mengmeng 5 ; Chen, Yanlian 6 ; Tian, Yuyang 6 ; Liu, Cihang 3 ; Shao, Dongxing 3 ; Jiang, Bin 3 ; Dou, Yali 7 ; Cong, Yusheng 2 ; Xing, Junyue 3 ; Zhang, Xiaotian 3 ; Xia, Yi 3 ; Zhou Songyang 6 ; Ma, Wenbin 6   VIAFID ORCID Logo  ; Zhao, Yong 6 ; Wang, Xian 8 ; Ma, Jinbiao 5   VIAFID ORCID Logo  ; Gorospe, Myriam 9 ; Ju, Zhenyu 2 ; Wang, Wengong 3   VIAFID ORCID Logo 

1  Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China 
2  Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China; Institute of Aging Research, Hangzhou Normal University, School of Medicine, Hangzhou, China 
3  Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China 
4  Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China 
5  Department of Biochemistry, School of life Sciences, Fudan University, Shanghai, China 
6  Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China 
7  Department of Pathology and Biological Chemistry, University of Michigan, Ann Arbor, MI, USA 
8  Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China 
9  Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA 
Pages
1-12
Publication year
2018
Publication date
Jun 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-04617-7
ProQuest document ID
2051644047
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.