Identification of mecciRNAs and their roles in the mitochondrial entry of proteins

Liu, Xu; Wang, Xiaolin; Li, Jingxin; Hu, Shanshan; Deng, Yuqi; Yin, Hong; Bao, Xichen; Zhang, Qiangfeng Cliff; Wang, Geng; Wang, Baolong; Shi, Qinghua; Ge, Shengfang

doi:10.1007/s11427-020-1631-9

Cited by 107 publications

(79 citation statements)

References 63 publications

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“…There are many different subclasses of circRNA and accumulating circRNA types have been identified on account of the advances in RNA extraction, library construction, RNA sequencing and analysis. For example, nuclear EIciRNAs (exon-intron type circRNAs) are involved in gene transcription [50], while mitochondrial mecciRNAs regulate the mitochondrial location of associated proteins [51]. rt-circRNA is a newly identified type of circRNA that is formed from exons originating from two adjacent genes on the same strand [40].…”

Section: Discussionmentioning

confidence: 99%

rtcisE2F drives liver TIC self-renewal and metastasis via m⁶A-modulated mRNA stability of E2F6 and E2F3

Chen

Huang

et al. 2021

Preprint

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BackgroundLiver tumor initiating cells (TICs) harbor self-renewal and differentiation capacities, and well contribute to liver tumorigenesis, metastasis and heterogeneity. However, the molecular mechanisms of liver TIC self-renewal are unclear. N6-methyladenosine is the most abundant modification of RNA molecules, and is involved in RNA stability and translation, but the molecular mechanisms of m6A regulation remain largely unknown.MethodscircRNA expression was detected by in situ hybridization, fluorescence in situ hybridization, quantitative real-time PCR and Northern blot. Target gene expression was examined by microarray analyses, quantitative real-time PCR and Western blot. CRISPR, CRISPR interference (CRISPRi) and short-hairpin RNA (shRNA) were used for circRNA/target gene knockout and knockdown. Liver TICs were enriched through sphere formation and FACS using CD133 as a marker, and liver TIC activity was assessed by tumor propagation, sphere formation, tumor-initiating, and transwell assays. Quantitative real-time PCR and Northern blot were used to determine mRNA stability. RNA–protein interactions were examined by RNA pulldown, RNA immunoprecipitation, Tagged RNA affinity purification (TRAP) and electrophoretic mobility shift assays (EMSA).ResultsHere, we identified a functional rt-circRNA, termed rtcisE2F, that is highly expressed in liver cancer and liver TICs. rtcisE2F plays essential roles in the self-renewal and activities of liver TICs. rtcisE2F targets E2F6 and E2F3 mRNAs, attenuates mRNA turnover, and increases E2F6/E2F3 expression. Mechanistically, rtcisE2F functions as a scaffold of m6A reader IGF2BP2 and E2F6/E2F3 mRNA, promotes the association of E2F6/E2F3 mRNAs with IGF2BP2, and then inhibits their association with another m6A reader, YTHDF2. IGF2BP2 inhibits E2F6/E2F3 mRNA decay, whereas YTHDF2 promotes E2F6/E2F3 mRNA decay. By switching m6A readers, rtcisE2F enhances E2F6/E2F3 mRNA stability. E2F6 and E2F3 are both required for liver TIC self-renewal and Wnt/β-catenin activation, and inhibition of these pathways is a potential strategy for preventing liver tumorigenesis and metastasis.ConclusionThis work identified rtcisE2F as a key modulator in liver cancer and liver TICs, providing evidence for the biological function of rt-circRNA and unveiling a new regulatory layer for liver TIC self-renewal. rtcisE2F is involved in E2F6/E2F3 stability by switching their binding to the m6A readers IGF2BP2 and YTHDF2, providing a competitive mechanism between RNA molecules and m6A readers. Both E2F6 and E2F3 are required for liver TIC self-renewal and serve as therapeutic targets for liver TIC elimination.

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Section: Discussionmentioning

confidence: 99%

rtcisE2F drives liver TIC self-renewal and metastasis via m⁶A-modulated mRNA stability of E2F6 and E2F3

Chen

Huang

et al. 2021

Preprint

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“…Mec-ciND1 interacts with nuclear coding proteins replication protein A32 (RPA32) and replication protein A70 (RPA70) to facilitate their insertion into mitochondria. Meanwhile, MecciND5 promotes the entry of hnRNPA1, hnRNPA2B1, and hnRNPA2B1 into mitochondria [82].…”

Section: Circrnas Participate In the Transportation Of Rbpsmentioning

confidence: 99%

CircRNA-Protein Interactions in Muscle Development and Diseases

Zheng¹,

Zhang²,

Odame³

et al. 2021

Preprint

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Muscle is one of the most critical organs for mammals, which governs multiple movement and physiological functions. Circular RNA (circRNA) is a kind of novel endogenous RNA without 5'-Caps and 3'-poly(A) structures formed by pre-mRNA's back-splicing. RNA binding proteins (RBPs) control the production and degradation of circRNA, help nucleus-cytoplasm transport and locate circRNA, and regulate circRNA translation. Therefore, circRNAs and the chaperoned RBPs play critical roles in muscle growth, development, and disease progression. In this review, we systematically characterize the possible molecular mechanism of circRNA-protein interactions. Also, we summarize the latest researches on circRNA-protein interactions in muscle development and diseases. Besides, we provide several valid prediction methods and experimental verification approaches. Our review reveals the importance of circRNAs and their protein chaperones and provides a reference for further study in this field.

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“…F-circEA is derived from the EML4-ALK fusion gene 21 . Additionally, circular DNA tumor virus and mitochondrial DNA produce circRNAs 22,23 .…”

Section: Other Sourcesmentioning

confidence: 99%

Biological roles and potential clinical values of circular RNAs in gastrointestinal malignancies

Xu¹,

Shao²,

Yan³

et al. 2021

Cancer Biol. Med.

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Circular RNAs (circRNAs), a class of endogenous RNA molecules, are produced by alternative splicing of precursor RNA and are covalently linked at the 5′ and 3′ ends. Recent studies have revealed that dysregulated circRNAs are closely related to the occurrence and progression of gastrointestinal malignancies. Accumulating evidence indicates that circRNAs, including circPVT1, circLARP4, circ-SFMBT2, cir-ITCH, circRNA_100782, circ_100395, circ-DONSON, hsa_circ_0001368, circNRIP1, circFAT1(e2), circCCDC66, circSMARCA5, circ-ZNF652, and circ_0030235 play important roles in the proliferation, differentiation, invasion, and metastasis of cancer cells through a variety of mechanisms, such as acting as microRNA sponges, interacting with RNA-binding proteins, regulating gene transcription and alternative splicing, and being translated into proteins. With the characteristics of high abundance, high stability, extensive functions, and certain tissue-, time-and diseasespecific expressions, circRNAs are expected to provide novel perspectives for the diagnoses and treatments of gastrointestinal malignancies.

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Identification of mecciRNAs and their roles in the mitochondrial entry of proteins

Cited by 107 publications

References 63 publications

rtcisE2F drives liver TIC self-renewal and metastasis via m⁶A-modulated mRNA stability of E2F6 and E2F3

rtcisE2F drives liver TIC self-renewal and metastasis via m⁶A-modulated mRNA stability of E2F6 and E2F3

CircRNA-Protein Interactions in Muscle Development and Diseases

Biological roles and potential clinical values of circular RNAs in gastrointestinal malignancies

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Identification of mecciRNAs and their roles in the mitochondrial entry of proteins

Cited by 107 publications

References 63 publications

rtcisE2F drives liver TIC self-renewal and metastasis via m6A-modulated mRNA stability of E2F6 and E2F3

rtcisE2F drives liver TIC self-renewal and metastasis via m6A-modulated mRNA stability of E2F6 and E2F3

CircRNA-Protein Interactions in Muscle Development and Diseases

Biological roles and potential clinical values of circular RNAs in gastrointestinal malignancies

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rtcisE2F drives liver TIC self-renewal and metastasis via m⁶A-modulated mRNA stability of E2F6 and E2F3

rtcisE2F drives liver TIC self-renewal and metastasis via m⁶A-modulated mRNA stability of E2F6 and E2F3