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PMID: 29279410 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

ALKBH5-dependent m6A demethylation controls splicing and stability of long 3'-UTR mRNAs in male germ cells.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 115 ·No. 2 ·2018-00-09 ·Pages E325-E333

Tang C, Klukovich R, Peng H, Wang Z, Yu T, Zhang Y, Zheng H, Klungland A, Yan W

Abstract

N6-methyladenosine (m6A) represents one of the most common RNA modifications in eukaryotes. Specific m6A writer, eraser, and reader proteins have been identified. As an m6A eraser, ALKBH5 specifically removes m6A from target mRNAs and inactivation of Alkbh5 leads to male infertility in mice. However, the underlying molecular mechanism remains unknown. Here, we report that ALKBH5-mediated m6A erasure in the nuclei of spermatocytes and round spermatids is essential for correct splicing and the production of longer 3'-UTR mRNAs, and failure to do so leads to aberrant splicing and production of shorter transcripts with elevated levels of m6A that are rapidly degraded. Our study identified reversible m6A modification as a critical mechanism of posttranscriptional control of mRNA fate in late meiotic and haploid spermatogenic cells.

Keywords
3′-UTR shortening RNA methylation alternative splicing fertility mRNA stability
MeSH Terms
3' Untranslated Regions AlkB Homolog 5, RNA Demethylase/genetics,metabolism Animals Demethylation Germ Cells Male Membrane Glycoproteins/genetics,metabolism Mice Mice, Knockout Nerve Tissue Proteins/genetics,metabolism RNA Splicing/physiology RNA, Messenger/genetics,metabolism Spermatocytes/physiology
Chemicals
3' Untranslated Regions Gpm6a protein, mouse Membrane Glycoproteins Nerve Tissue Proteins RNA, Messenger ALKBH5 protein, mouse AlkB Homolog 5, RNA Demethylase
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Tang Chong
Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV 89557.
Klukovich Rachel
Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV 89557.
Peng Hongying
Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV 89557.
Wang Zhuqing
Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV 89557.
Yu Tian
Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV 89557.
Zhang Ying
Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV 89557.
Zheng Huili
Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV 89557.
Klungland Arne
Department of Microbiology, Oslo University Hospital, Rikshospitalet, 0027 Oslo, Norway. | Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway.
Yan Wei
Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV 89557; wyan@med.unr.edu. | Department of Biology, University of Nevada, Reno, Reno, NV 89557.
Conflict of Interest

The authors declare no conflict of interest.

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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1717794115
Email
wyan@med.unr.edu
Published
2018-00-09
Epub
2017-00-26
Pages
E325-E333
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC5777073
Subset
IM
Grants
NIGMS NIH HHS · P30 GM110767 · United States
NICHD NIH HHS · R01 HD060858 · United States
NICHD NIH HHS · R01 HD085506 · United States
NICHD NIH HHS · R21 HD071736 · United States
External Links
PubMed source DOI: 10.1073/pnas.1717794115 PMC Full Text View journal details
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