A Circular RNA from the MDM2 Locus Controls Cell Cycle Progression by Suppressing p53 Levels

Circular RNAs (circRNAs) are a class of noncoding RNAs produced by a noncanonical form of alternative splicing called back-splicing. To investigate a potential role of circRNAs in the p53 pathway, we analyzed RNA sequencing (RNA-seq) data from colorectal cancer cell lines (HCT116, RKO, and SW48) tha...

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Published inMolecular and cellular biology Vol. 40; no. 9
Main Authors Chaudhary, Ritu, Muys, Bruna R., Grammatikakis, Ioannis, De, Supriyo, Abdelmohsen, Kotb, Li, Xiao Ling, Zhu, Yuelin, Daulatabad, Swapna Vidhur, Tsitsipatis, Dimitrios, Meltzer, Paul S., Gorospe, Myriam, Janga, Sarath Chandra, Lal, Ashish
Format Journal Article
LanguageEnglish
Published United States Taylor & Francis 13.04.2020
American Society for Microbiology
Subjects
cell cycle
circRNA
circular RNA
CRC
DNA damage
MDM2
Spotlight
circRNA
CRC
cell cycle
DNA damage
circular RNA
MDM2
p53
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Summary:Circular RNAs (circRNAs) are a class of noncoding RNAs produced by a noncanonical form of alternative splicing called back-splicing. To investigate a potential role of circRNAs in the p53 pathway, we analyzed RNA sequencing (RNA-seq) data from colorectal cancer cell lines (HCT116, RKO, and SW48) that were untreated or treated with a DNA-damaging agent. Surprisingly, unlike the strong p53-dependent induction of hundreds of p53-induced mRNAs upon DNA damage, only a few circRNAs were upregulated from p53-induced genes. circ-MDM2, an annotated circRNA from the MDM2 locus, was one of the handful of circRNAs that originated from a p53-induced gene. Given the central role of MDM2 in suppressing p53 protein levels and p53 activity, we investigated the function of circ-MDM2. Knocking down circ-MDM2 with small interfering RNAs (siRNAs) that targeted circ-MDM2 did not alter MDM2 mRNA or MDM2 protein levels but resulted in increased basal p53 levels and growth defects in vitro and in vivo. Consistent with these results, transcriptome profiling showed increased expression of several direct p53 targets, reduced retinoblastoma protein (Rb) phosphorylation, and defects in G 1 -S progression upon silencing circ-MDM2. Our results on the initial characterization of circ-MDM2 identify a new player from the MDM2 locus that suppresses p53 levels and cell cycle progression.
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Present address: Ritu Chaudhary, Department of Head and Neck-Endocrine Oncology, Moffitt Cancer Center, Tampa, Florida, USA.
Ritu Chaudhary, Bruna R. Muys, and Ioannis Grammatikakis contributed equally to this work. Ritu Chaudhary performed most of the initial experiments, Bruna Muys performed experiments and helped in editing the initial submission, and Ioannis Grammatikakis performed majority of the experiments during the revision and edited the text during the revision.
Citation Chaudhary R, Muys BR, Grammatikakis I, De S, Abdelmohsen K, Li XL, Zhu Y, Daulatabad SV, Tsitsipatis D, Meltzer PS, Gorospe M, Janga SC, Lal A. 2020. A circular RNA from the MDM2 locus controls cell cycle progression by suppressing p53 levels. Mol Cell Biol 40:e00473-19. https://doi.org/10.1128/MCB.00473-19.
ISSN:1098-5549
0270-7306
1098-5549
DOI:10.1128/MCB.00473-19