Volume 27, No 9, Sep 2017

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 27 Issue 9, September 2017: 1115-1127

ORIGINAL ARTICLES

Ythdc2 is an N⁶-methyladenosine binding protein that regulates mammalian spermatogenesis

Phillip J Hsu^1,2,3,*, Yunfei Zhu^4,*, Honghui Ma^1,2,*, Yueshuai Guo^4,*, Xiaodan Shi⁴, Yuanyuan Liu⁴, Meijie Qi⁴, Zhike Lu^1,2, Hailing Shi^1,2, Jianying Wang⁴, Yiwei Cheng⁴, Guanzheng Luo^1,2, Qing Dai^1,2, Mingxi Liu⁴, Xuejiang Guo⁴, Jiahao Sha⁴, Bin Shen⁴ and Chuan He^1,2,5

¹Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA;
²Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA;
³Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA;
⁴State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing 211166, China;
⁵Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA Correspondence: Chuan He, E-mail: chuanhe@uchicago.edu; Bin Shen, E-mail: (binshen@njmu.edu.cn)

N6-methyladenosine (m⁶A) is the most common internal modification in eukaryotic mRNA. It is dynamically installed and removed, and acts as a new layer of mRNA metabolism, regulating biological processes including stem cell pluripotency, cell differentiation, and energy homeostasis. m⁶A is recognized by selective binding proteins; YTHDF1 and YTHDF3 work in concert to affect the translation of m⁶A-containing mRNAs, YTHDF2 expedites mRNA decay, and YTHDC1 affects the nuclear processing of its targets. The biological function of YTHDC2, the final member of the YTH protein family, remains unknown. We report that YTHDC2 selectively binds m⁶A at its consensus motif. YTHDC2 enhances the translation efficiency of its targets and also decreases their mRNA abundance. Ythdc2 knockout mice are infertile; males have significantly smaller testes and females have significantly smaller ovaries compared to those of littermates. The germ cells of Ythdc2 knockout mice do not develop past the zygotene stage and accordingly, Ythdc2 is upregulated in the testes as meiosis begins. Thus, YTHDC2 is an m⁶A-binding protein that plays critical roles during spermatogenesis.

10.1038/cr.2017.99

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