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

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 replicativ...

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Main Authors:	Tang, Hao, Fan, Xiuqin, Xing, Junyue, Liu, Zhenyun, Jiang, Bin, Dou, Yali, Gorospe, Myriam, Wang, Wengong
Format:	Online
Language:	English
Published:	Impact Journals LLC 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712338/

id	pubmed-4712338
recordtype	oai_dc
spelling	pubmed-47123382016-01-25 NSun2 delays replicative senescence by repressing p27 (KIP1) translation and elevating CDK1 translation Tang, Hao Fan, Xiuqin Xing, Junyue Liu, Zhenyun Jiang, Bin Dou, Yali Gorospe, Myriam Wang, Wengong Research Paper 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. Impact Journals LLC 2015-12-14 /pmc/articles/PMC4712338/ /pubmed/26687548 Text en Copyright: © 2015 Tang et al. http://creativecommons.org/licenses/by/2.5/ 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.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Tang, Hao Fan, Xiuqin Xing, Junyue Liu, Zhenyun Jiang, Bin Dou, Yali Gorospe, Myriam Wang, Wengong
spellingShingle	Tang, Hao Fan, Xiuqin Xing, Junyue Liu, Zhenyun Jiang, Bin Dou, Yali Gorospe, Myriam Wang, Wengong NSun2 delays replicative senescence by repressing p27 (KIP1) translation and elevating CDK1 translation
author_facet	Tang, Hao Fan, Xiuqin Xing, Junyue Liu, Zhenyun Jiang, Bin Dou, Yali Gorospe, Myriam Wang, Wengong
author_sort	Tang, Hao
title	NSun2 delays replicative senescence by repressing p27 (KIP1) translation and elevating CDK1 translation
title_short	NSun2 delays replicative senescence by repressing p27 (KIP1) translation and elevating CDK1 translation
title_full	NSun2 delays replicative senescence by repressing p27 (KIP1) translation and elevating CDK1 translation
title_fullStr	NSun2 delays replicative senescence by repressing p27 (KIP1) translation and elevating CDK1 translation
title_full_unstemmed	NSun2 delays replicative senescence by repressing p27 (KIP1) translation and elevating CDK1 translation
title_sort	nsun2 delays replicative senescence by repressing p27 (kip1) translation and elevating cdk1 translation
description	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.
publisher	Impact Journals LLC
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712338/
_version_	1613523870569988096

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

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