title: Coordinated control of senescence by lncRNA and a novel T-box3 co-repressor complex.
abstract: Cellular senescence is a crucial tumor suppressor mechanism. We discovered a CAPERα/TBX3 repressor complex required to prevent senescence in primary cells and mouse embryos. Critical, previously unknown roles for CAPERα in controlling cell proliferation are manifest in an obligatory interaction with TBX3 to regulate chromatin structure and repress transcription of CDKN2A-p16INK and the RB pathway. The IncRNA UCA1 is a direct target of CAPERα/TBX3 repression whose overexpression is sufficient to induce senescence. In proliferating cells, we found that hnRNPA1 binds and destabilizes CDKN2A-p16INK mRNA whereas during senescence, UCA1 sequesters hnRNPA1 and thus stabilizes CDKN2A-p16INK. Thus CAPERα/TBX3 and UCA1 constitute a coordinated, reinforcing mechanism to regulate both CDKN2A-p16INK transcription and mRNA stability. Dissociation of the CAPERα/TBX3 co-repressor during oncogenic stress activates UCA1, revealing a novel mechanism for oncogene-induced senescence. Our elucidation of CAPERα and UCA1 functions in vivo provides new insights into senescence induction, and the oncogenic and developmental properties of TBX3.
authors.affiliation: Weis Center for Research, Geisinger Clinic, Danville, United States.
authors.forename: Pavan
authors.initials: P
authors.lastname: Kumar P
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, United States.
authors.forename: Uchenna
authors.initials: U
authors.lastname: Emechebe
authors.affiliation: The Centre for Children's Cancer Research, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Smith
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Franklin
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, United States.
authors.forename: Barry
authors.initials: B
authors.lastname: Moore
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Yandell
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, United States.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Lessnick
authors.affiliation: Weis Center for Research, Geisinger Clinic, Danville, United States.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Moon
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D016922:Cellular Senescence; D002843:Chromatin / Q000737:chemistry; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism*; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D009857:Oncogenes; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D062085:RNA, Long Noncoding / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000378:metabolism*
chemical_list: D002843:Chromatin; D019941:Cyclin-Dependent Kinase Inhibitor p16; C084105:HCC1 autoantigen; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C000619657:Hnrnpa1 protein, mouse; D009687:Nuclear Proteins; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D020825:T-Box Domain Proteins; C106884:TBX3 protein, human; C491460:Tbx3 protein, mouse; C515159:UCA1 RNA, human; C000619656:hnRNPA1 protein, human
keywords: cell biology; development; developmental biology; mouse; oncogenesis; p16; senescence; stem cells