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

PLoS One. 2014 Apr 18;9(4):e95216. doi: 10.1371/journal.pone.0095216. eCollection 2014.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • RNA, Long Noncoding / metabolism
  • RNA, Small Interfering / genetics

Substances

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