A new lncRNA, APTR, associates with and represses the CDKN1A/p21 promoter by recruiting polycomb proteins

Long noncoding RNAs (lncRNAs) have emerged as a major regulator of cell physiology, but many of which have no known function. CDKN1A/p21 is an important inhibitor of the cell-cycle, regulator of the DNA damage response and effector of the tumor suppressor p53, playing a crucial role in tumor develop...

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Bibliographic Details
Published in:PloS one 2014-04, Vol.9 (4), p.e95216-e95216
Main Authors: Negishi, Masamitsu, Wongpalee, Somsakul P, Sarkar, Sukumar, Park, Jonghoon, Lee, Kyung Yong, Shibata, Yoshiyuki, Reon, Brian J, Abounader, Roger, Suzuki, Yutaka, Sugano, Sumio, Dutta, Anindya
Format: Article
Language:English
Subjects:
Alu elements
Base Sequence
Biochemistry
Biology and life sciences
Brain cancer
Cancer
Cell cycle
Cell growth
Cell Line
Cell Proliferation
Chromatin Immunoprecipitation
Coding
Cyclin-dependent kinase inhibitor p21
Cyclin-Dependent Kinase Inhibitor p21 - genetics
Deoxyribonucleic acid
DNA
DNA damage
DNA Primers
Doxorubicin
Epigenetics
Gene expression
Gene Silencing
Genetic screening
Heat stress
Heat tolerance
Humans
Inhibitors
Kinases
Localization
Medicine
p53 Protein
Polycomb group proteins
Polycomb Repressive Complex 2 - metabolism
Polymerase Chain Reaction
Promoter Regions, Genetic
Proteins
RNA, Long Noncoding - genetics
RNA, Long Noncoding - metabolism
RNA, Small Interfering - genetics
siRNA
Tumor cell lines
Tumor suppressor genes
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Summary:Long noncoding RNAs (lncRNAs) have emerged as a major regulator of cell physiology, but many of which have no known function. CDKN1A/p21 is an important inhibitor of the cell-cycle, regulator of the DNA damage response and effector of the tumor suppressor p53, playing a crucial role in tumor development and prevention. In order to identify a regulator for tumor progression, we performed an siRNA screen of human lncRNAs required for cell proliferation, and identified a novel lncRNA, APTR, that acts in trans to repress the CDKN1A/p21 promoter independent of p53 to promote cell proliferation. APTR associates with the promoter of CDKN1A/p21 and this association requires a complementary-Alu sequence encoded in APTR. A different module of APTR associates with and recruits the Polycomb repressive complex 2 (PRC2) to epigenetically repress the p21 promoter. A decrease in APTR is necessary for the induction of p21 after heat stress and DNA damage by doxorubicin, and the levels of APTR and p21 are anti-correlated in human glioblastomas. Our data identify a new regulator of the cell-cycle inhibitor CDKN1A/p21 that acts as a proliferative factor in cancer cell lines and in glioblastomas and demonstrate that Alu elements present in lncRNAs can contribute to targeting regulatory lncRNAs to promoters.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0095216