A novel long noncoding RNA Linc-ASEN represses cellular senescence through multileveled reduction of p21 expression

Hyung Chul Lee; Donghee Kang; Namshik Han; Yerim Lee; Hyun Jung Hwang; Sat Byol Lee; Jueng Soo You; Byung Soh Min; Heon Joo Park; Young Gyu Ko; Myriam Gorospe; Jae Seon Lee

doi:10.1038/s41418-019-0467-6

A novel long noncoding RNA Linc-ASEN represses cellular senescence through multileveled reduction of p21 expression

Hyung Chul Lee
, Donghee Kang
, Namshik Han
, Yerim Lee
, Hyun Jung Hwang
, Sat Byol Lee
, Jueng Soo You
, Byung Soh Min
, Heon Joo Park
, Young Gyu Ko
, Myriam Gorospe
, Jae Seon Lee^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

28 Citations (Scopus)

Abstract

Long noncoding RNAs (lncRNAs) regulating diverse cellular processes implicate in many diseases. However, the function of lncRNAs in cellular senescence remains largely unknown. Here we identify a novel long intergenic noncoding RNA Linc-ASEN expresses in prematurely senescent cells. We find that Linc-ASEN associates with UPF1 by RNA pulldown mass spectrometry analysis, and represses cellular senescence by reducing p21 production transcriptionally and posttranscriptionally. Mechanistically, the Linc-ASEN-UPF1 complex suppressed p21 transcription by recruiting Polycomb Repressive Complex 1 (PRC1) and PRC2 to the p21 locus, and thereby preventing binding of the transcriptional activator p53 on the p21 promoter through histone modification. In addition, the Linc-ASEN-UPF1 complex repressed p21 expression posttranscriptionally by enhancing p21 mRNA decay in association with DCP1A. Accordingly, Linc-ASEN levels were found to correlate inversely with p21 mRNA levels in tumors from patient-derived mouse xenograft, in various human cancer tissues, and in aged mice tissues. Our results reveal that Linc-ASEN prevents cellular senescence by reducing the transcription and stability of p21 mRNA in concert with UPF1, and suggest that Linc-ASEN might be a potential therapeutic target in processes influenced by senescence, including cancer.

Original language	English
Pages (from-to)	1844-1861
Number of pages	18
Journal	Cell Death and Differentiation
Volume	27
Issue number	6
DOIs	https://doi.org/10.1038/s41418-019-0467-6
Publication status	Published - 2020 Jun 1

Bibliographical note

Publisher Copyright:
© 2019, The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1038/s41418-019-0467-6

Cite this

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title = "A novel long noncoding RNA Linc-ASEN represses cellular senescence through multileveled reduction of p21 expression",

abstract = "Long noncoding RNAs (lncRNAs) regulating diverse cellular processes implicate in many diseases. However, the function of lncRNAs in cellular senescence remains largely unknown. Here we identify a novel long intergenic noncoding RNA Linc-ASEN expresses in prematurely senescent cells. We find that Linc-ASEN associates with UPF1 by RNA pulldown mass spectrometry analysis, and represses cellular senescence by reducing p21 production transcriptionally and posttranscriptionally. Mechanistically, the Linc-ASEN-UPF1 complex suppressed p21 transcription by recruiting Polycomb Repressive Complex 1 (PRC1) and PRC2 to the p21 locus, and thereby preventing binding of the transcriptional activator p53 on the p21 promoter through histone modification. In addition, the Linc-ASEN-UPF1 complex repressed p21 expression posttranscriptionally by enhancing p21 mRNA decay in association with DCP1A. Accordingly, Linc-ASEN levels were found to correlate inversely with p21 mRNA levels in tumors from patient-derived mouse xenograft, in various human cancer tissues, and in aged mice tissues. Our results reveal that Linc-ASEN prevents cellular senescence by reducing the transcription and stability of p21 mRNA in concert with UPF1, and suggest that Linc-ASEN might be a potential therapeutic target in processes influenced by senescence, including cancer.",

author = "Lee, \{Hyung Chul\} and Donghee Kang and Namshik Han and Yerim Lee and Hwang, \{Hyun Jung\} and Lee, \{Sat Byol\} and You, \{Jueng Soo\} and Min, \{Byung Soh\} and Park, \{Heon Joo\} and Ko, \{Young Gyu\} and Myriam Gorospe and Lee, \{Jae Seon\}",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.",

year = "2020",

month = jun,

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doi = "10.1038/s41418-019-0467-6",

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T1 - A novel long noncoding RNA Linc-ASEN represses cellular senescence through multileveled reduction of p21 expression

AU - Lee, Hyung Chul

AU - Kang, Donghee

AU - Han, Namshik

AU - Lee, Yerim

AU - Hwang, Hyun Jung

AU - Lee, Sat Byol

AU - You, Jueng Soo

AU - Min, Byung Soh

AU - Park, Heon Joo

AU - Ko, Young Gyu

AU - Gorospe, Myriam

AU - Lee, Jae Seon

PY - 2020/6/1

Y1 - 2020/6/1

N2 - Long noncoding RNAs (lncRNAs) regulating diverse cellular processes implicate in many diseases. However, the function of lncRNAs in cellular senescence remains largely unknown. Here we identify a novel long intergenic noncoding RNA Linc-ASEN expresses in prematurely senescent cells. We find that Linc-ASEN associates with UPF1 by RNA pulldown mass spectrometry analysis, and represses cellular senescence by reducing p21 production transcriptionally and posttranscriptionally. Mechanistically, the Linc-ASEN-UPF1 complex suppressed p21 transcription by recruiting Polycomb Repressive Complex 1 (PRC1) and PRC2 to the p21 locus, and thereby preventing binding of the transcriptional activator p53 on the p21 promoter through histone modification. In addition, the Linc-ASEN-UPF1 complex repressed p21 expression posttranscriptionally by enhancing p21 mRNA decay in association with DCP1A. Accordingly, Linc-ASEN levels were found to correlate inversely with p21 mRNA levels in tumors from patient-derived mouse xenograft, in various human cancer tissues, and in aged mice tissues. Our results reveal that Linc-ASEN prevents cellular senescence by reducing the transcription and stability of p21 mRNA in concert with UPF1, and suggest that Linc-ASEN might be a potential therapeutic target in processes influenced by senescence, including cancer.

AB - Long noncoding RNAs (lncRNAs) regulating diverse cellular processes implicate in many diseases. However, the function of lncRNAs in cellular senescence remains largely unknown. Here we identify a novel long intergenic noncoding RNA Linc-ASEN expresses in prematurely senescent cells. We find that Linc-ASEN associates with UPF1 by RNA pulldown mass spectrometry analysis, and represses cellular senescence by reducing p21 production transcriptionally and posttranscriptionally. Mechanistically, the Linc-ASEN-UPF1 complex suppressed p21 transcription by recruiting Polycomb Repressive Complex 1 (PRC1) and PRC2 to the p21 locus, and thereby preventing binding of the transcriptional activator p53 on the p21 promoter through histone modification. In addition, the Linc-ASEN-UPF1 complex repressed p21 expression posttranscriptionally by enhancing p21 mRNA decay in association with DCP1A. Accordingly, Linc-ASEN levels were found to correlate inversely with p21 mRNA levels in tumors from patient-derived mouse xenograft, in various human cancer tissues, and in aged mice tissues. Our results reveal that Linc-ASEN prevents cellular senescence by reducing the transcription and stability of p21 mRNA in concert with UPF1, and suggest that Linc-ASEN might be a potential therapeutic target in processes influenced by senescence, including cancer.

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A novel long noncoding RNA Linc-ASEN represses cellular senescence through multileveled reduction of p21 expression

Abstract

Bibliographical note

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ASJC Scopus subject areas

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