Identification of senescence-associated circular RNAs (SAC-RNAs) reveals senescence suppressor CircPVT1

Nucleic Acids Res. 2017 Apr 20;45(7):4021-4035. doi: 10.1093/nar/gkw1201.


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.

MeSH terms

  • Cell Line
  • Cell Proliferation
  • Cellular Senescence / genetics*
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Humans
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / metabolism
  • RNA / metabolism*
  • RNA, Circular
  • RNA, Long Noncoding / metabolism*


  • MicroRNAs
  • PVT1 long-non-coding RNA, human
  • RNA, Circular
  • RNA, Long Noncoding
  • mirnlet7 microRNA, human
  • RNA