Abstract
Circular RNAs (CircRNAs) are a novel subset of non-coding RNA widely present in eukaryotes that play a central role in physiological and pathological conditions. Accumulating evidence has indicated that CircRNAs participated in modulating tumorigenesis by acting as a competing endogenous RNA (CeRNA). However, the roles and functions of CircRNAs in cellular senescence and aging of organisms remain largely obscure. We performed whole transcriptome sequencing to compare the expression patterns of circular RNAs in young and prematurely senescent human diploid fibroblast 2BS cells, and identified senescence-associated circRNAs (SAC-RNAs). Among these SAC-RNAs, we observed the significantly downregulated expression of CircRNAs originating from exons 6 and 7 circularization of the cyclin B1 gene (CCNB1), termed CircCCNB1. Reduced CircCCNB1 expression triggered senescence in young 2BS cells, as measured by increased senescence associated-beta-galactosidase (SA-β-gal) activity, enhanced expression of cyclin-dependent kinase inhibitor 1A (CDKN1A)/P21 and tumor protein 53 (TP53) expression, and reduced cell proliferation. Mechanistically, reduced CircCCNB1 level inhibited cyclin E2 (CCNE2) expression by modulating micro RNA (miR)-449a activity, which repressed cellular proliferation. Our data suggested that CircCCNB1may serve as a sponge against miR-449a to delay cellular senescence by targeting CCNE2. Targeting CircCCNB1 may represent a promising strategy for aging and age-related disease interventions. Furthermore, we also identified and characterized several kinds of the CircCCNB1-binding proteins (CBPs), which may contribute to the degradation of CircCCNB1.
Highlights
Cellular senescence is a permanent and irreversible growth arrest, which is divided into replicative cellular senescence or premature cellular senescence [1]
Most of these CircRNAs originated from protein coding exons, while others aligned with introns or unknown sequences (Figure 1B)
As cell cycle progression is a crucial characteristic of cellular senescence, we focused our attention on CircCCNB1 and cyclin E2 (CCNE2) in cellular senescence
Summary
Cellular senescence is a permanent and irreversible growth arrest, which is divided into replicative cellular senescence or premature cellular senescence [1]. After completing a limited number of divisions, eukaryotic cells retain their basic metabolism, but lose the ability to synthesize DNA, leading to the exhaustion of their proliferative potential and telomere erosion, a phenomenon termed ‘replicative senescence’ [2]. External stress can induce cellular senescence called ‘premature senescence’, which is independent of telomere erosion, such stress including oncogene overexpression, ionizing radiation, oxidative stress, etc. Cellular senescence is mainly measured by (I) irreversible growth arrest; (II) altered cellular morphology; (III) senescenceassociated β-galactosidase (SA-β-gal) activity; (IV) senescence-associated heterochromatin foci (SAHF); (V). P53-P21CIP1 and P16INK4A-Rb comprise of the major signaling pathway regulating cellular senescence. P53 and P16INK4A, are considered crucial regulatory factors for the induction of cellular senescence [5]
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