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

Abstract

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.

• Authors: Masamitsu Negishi, Somsakul P Wongpalee, Sukumar Sarkar, Jonghoon Park, Kyung Yong Lee, Yoshiyuki Shibata, Brian J Reon, Roger Abounader, Yutaka Suzuki, Sumio Sugano, Anindya Dutta
• Journal: PloS one (PLoS One) Vol. 9 Issue 4 Pg. e95216 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24748121 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• DNA Primers
• MTF2 protein, human
• RNA, Long Noncoding
• RNA, Small Interfering
• Polycomb Repressive Complex 2

Topics

• Base Sequence
• Cell Line
• Cell Proliferation
• Chromatin Immunoprecipitation
• Cyclin-Dependent Kinase Inhibitor p21 (genetics)
• DNA Primers
• Gene Silencing
• Humans
• Polycomb Repressive Complex 2 (metabolism)
• Polymerase Chain Reaction
• Promoter Regions, Genetic
• RNA, Long Noncoding (genetics, metabolism)
• RNA, Small Interfering (genetics)