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Research Paper|Volume 7, Issue 12|pp 1143—1155

NSun2 delays replicative senescence by repressing p27 (KIP1) translation and elevating CDK1 translation

Hao Tang1, Xiuqin Fan1, Junyue Xing1, Zhenyun Liu1, Bin Jiang1, Yali Dou2, Myriam Gorospe3, Wengong Wang1
  • 1Department 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 100191,China
  • 2Department of Pathology and Biological Chemistry, University of Michigan, MSI 5215A, Ann Arbor, MI 48105, USA
  • 3Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
Received: October 25, 2015Accepted: November 30, 2015Published: December 14, 2015
https://doi.org/10.18632/aging.100860

Copyright: © 2015 Tang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

A rise in the levels of the cyclin-dependent kinase (CDK) inhibitor p27KIP1 is important for the growth arrest of senescent cells, but the mechanisms responsible for this increase are poorly understood. Here, we show that the tRNA methyltransferase NSun2 represses the expression of p27 in replicative senescence. NSun2 methylated the 5′-untranslated region (UTR) of p27 mRNA at cytosine C64 in vitro and in cells, thereby repressing the translation of p27. During replicative senescence, increased p27 protein levels were accompanied by decreased NSun2 protein levels. Knockdown of NSun2 in human diploid fibroblasts (HDFs) elevated p27 levels and reduced the expression of CDK1 (encoded by CDK1 mRNA, a previously reported target of NSun2), which in turn further repressed cell proliferation and accelerated replicative senescence, while overexpression of NSun2 exerted the opposite effect. Ectopic overexpression of the p27 5′UTR fragment rescued the effect of NSun2 overexpression in lowering p27, increasing CDK1, promoting cell proliferation, and delaying replicative senescence. Our findings indicate that NSun2-mediated mRNA methylation regulates p27 and CDK1 levels during replicative senescence.