Circular RNA CircCCNB1 sponges micro RNA-449a to inhibit cellular senescence by targeting CCNE2
Circular RNA CircCCNB1 sponges micro RNA-449a to inhibit cellular senescence by targeting CCNE2
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环状RNA CircCCNB1海绵微小RNA-449a通过靶向CCNE2抑制细胞衰老
DOI：
10.18632/aging.102449
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发表时间：
2019-11-30
期刊：
影响因子：
5.2
通讯作者：
Mao, Ze Bin
中科院分区：
文献类型：
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作者：
Yu, Ai Qing;Wang, Zhi Xiao;Mao, Ze Bin
环状RNA（CircRNA）是一类广泛存在于真核生物中的非编码RNA，在生理和病理过程中起着重要作用。越来越多的证据表明，CircRNA通过作为竞争性内源性RNA（CeRNA）参与调节肿瘤发生。然而，CircRNA在细胞衰老和生物体衰老中的作用和功能在很大程度上仍然不清楚。我们进行了全转录组测序，以比较年轻和过早衰老的人二倍体成纤维细胞2BS细胞中环状RNA的表达模式，并鉴定了衰老相关的环状RNA（SAC-RNA）。在这些SAC-RNA中，我们观察到来自细胞周期蛋白B1基因（CCNB 1）的外显子6和7环化的CircRNA（称为CircCCNB 1）的表达显著下调。CircCCNB 1表达减少引发年轻2BS细胞衰老，如通过增加衰老相关β-半乳糖苷酶（SA-β-gal）活性、增加细胞周期蛋白依赖性激酶抑制剂1A（CDKN 1A）/P21表达和肿瘤蛋白53（TP 53）表达以及减少细胞增殖所测量的。从机制上讲，降低CircCCNB 1水平通过调节microRNA（miR）-449a活性抑制细胞周期蛋白E2（CCNE 2）表达，从而抑制细胞增殖。我们的数据表明，CircCCNB 1可能作为海绵针对miR-449 a，通过靶向CCNE 2延缓细胞衰老。靶向CircCCNB 1可能是衰老和年龄相关疾病干预的一种有前途的策略。此外，我们还鉴定和表征了几种CircCCNB 1结合蛋白（CBPs），这可能有助于CircCCNB 1的降解。
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.