title: 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.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Negishi
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
authors.forename: Somsakul P
authors.initials: SP
authors.lastname: Wongpalee
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
authors.forename: Sukumar
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
authors.forename: Jonghoon
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
authors.forename: Kyung Yong
authors.initials: KY
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Shibata
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Reon
authors.affiliation: Department of Microbiology, Neurology, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Roger
authors.initials: R
authors.lastname: Abounader
authors.affiliation: The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Sumio
authors.initials: S
authors.lastname: Sugano
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
authors.forename: Anindya
authors.initials: A
authors.lastname: Dutta
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D017931:DNA Primers; D020868:Gene Silencing; D006801:Humans; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017931:DNA Primers; C570567:MTF2 protein, human; D062085:RNA, Long Noncoding; D034741:RNA, Small Interfering; D063151:Polycomb Repressive Complex 2
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