title: Identification of senescence-associated circular RNAs (SAC-RNAs) reveals senescence suppressor CircPVT1.
abstract: Using RNA sequencing (RNA-Seq), we compared the expression patterns of circular RNAs in proliferating (early-passage) and senescent (late-passage) human diploid WI-38 fibroblasts. Among the differentially expressed senescence-associated circRNAs (which we termed 'SAC-RNAs'), we identified CircPVT1, generated by circularization of an exon of the PVT1 gene, as a circular RNA showing markedly reduced levels in senescent fibroblasts. Reducing CircPVT1 levels in proliferating fibroblasts triggered senescence, as determined by a rise in senescence-associated β-galactosidase activity, higher abundance of CDKN1A/P21 and TP53, and reduced cell proliferation. Although several microRNAs were predicted to bind CircPVT1, only let-7 was found enriched after pulldown of endogenous CircPVT1, suggesting that CircPVT1 might selectively modulate let-7 activity and hence expression of let-7-regulated mRNAs. Reporter analysis revealed that CircPVT1 decreased the cellular pool of available let-7, and antagonizing endogenous let-7 triggered cell proliferation. Importantly, silencing CircPVT1 promoted cell senescence and reversed the proliferative phenotype observed after let-7 function was impaired. Consequently, the levels of several proliferative proteins that prevent senescence, such as IGF2BP1, KRAS and HMGA2, encoded by let-7 target mRNAs, were reduced by silencing CircPVT1. Our findings indicate that the SAC-RNA CircPVT1, elevated in dividing cells and reduced in senescent cells, sequesters let-7 to enable a proliferative phenotype.
authors.affiliation: Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Amaresh C
authors.initials: AC
authors.lastname: Panda
authors.affiliation: Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Grammatikakis
authors.affiliation: Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Kyoung Mi
authors.initials: KM
authors.lastname: Kim
authors.affiliation: Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Supriyo
authors.initials: S
authors.lastname: De
authors.affiliation: Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Martindale
authors.affiliation: Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Munk
authors.affiliation: Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Yang
authors.affiliation: Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Kotb
authors.initials: K
authors.lastname: Abdelmohsen
authors.affiliation: Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Myriam
authors.initials: M
authors.lastname: Gorospe
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism; D012313:RNA / Q000378:metabolism*; D000079962:RNA, Circular; D062085:RNA, Long Noncoding / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; C521123:PVT1 long-non-coding RNA, human; D000079962:RNA, Circular; D062085:RNA, Long Noncoding; C487931:mirnlet7 microRNA, human; D012313:RNA