Abstract
Long noncoding RNAs constitute a major fraction of the eukaryotic transcriptome, and together with proteins, they intricately fine-tune various growth regulatory signals to control cellular homeostasis. Here, we describe the functional characterisation of a novel pair of long intergenic noncoding RNAs (lincRNAs) comprised of complementary, fully overlapping sense and antisense transcripts Genomic Instability Inducing RNA (Ginir) and antisense RNA of Ginir (Giniras), respectively, from mouse cells. This transcript pair is expressed in a spatiotemporal manner during embryonic development. The individual levels of the sense and antisense transcripts are finely balanced during embryonic growth and in adult tissues. Functional studies of the individual transcripts performed using overexpression and knock-down strategies in mouse cells has led to the discovery that Ginir RNA is a regulator of cellular proliferation and can act as an oncogene having a preeminent role in malignant transformation. Mechanistically, we demonstrate that the oncogenic function of Ginir is mediated by its interaction with centrosomal protein 112 (Cep112). Additionally, we establish here a specific interaction between Cep112 with breast cancer type 1 susceptibility protein (Brca1), another centrosome-associated protein. Next, we prove that the mutual interaction between Cep112 with Brca1 is significant for mitotic regulation and maintenance of genomic stability. Furthermore, we demonstrate that the Cep112 protein interaction with Brca1 protein is impaired when an elevated level of Ginir RNA is present in the cells, resulting in severe deregulation and abnormality in mitosis, leading to malignant transformation. Inhibiting the Ginir RNA function in transformed cells attenuates transformation and restores genomic stability. Together, these findings unravel, to our knowledge, a hitherto-unknown mechanism of oncogenesis mediated by a long noncoding RNA and establishes a unique role of Cep112–Brca1 interaction being modulated by Ginir RNA in maintaining mitotic fidelity.
Highlights
The recent surge of information regarding evolutionary conservation, functionality, and annotation of sequences from the mammalian genome has revealed that a bulk of the transcriptome is noncoding and includes small and long noncoding RNAs
We find that Genomic Instability Inducing RNA (Ginir) acts as a dominant oncogene when Ginir transcript levels are overexpressed in mouse fibroblasts and that centrosomal protein 112 (Cep112) is its interacting protein partner
We report that Cep112 interacts with breast cancer type 1 susceptibility protein (Brca1), a protein well known for its role in genome surveillance
Summary
The recent surge of information regarding evolutionary conservation, functionality, and annotation of sequences from the mammalian genome has revealed that a bulk of the transcriptome is noncoding and includes small and long noncoding RNAs (lncRNAs). The varied mechanisms through which they mediate gene regulation range from adenocarcinoma transcript 1; MAGE, the melanoma antigen gene; MALAT1, metastasis associated lung adenocarcinoma transcript 1; MALDI-TOF, matrix-assisted laser desorption ionisation time-of-flight mass spectrometry; MHM, male hypermethylated; Mre, meiotic recombination 11; MTT, 3-(4, 5-dimethylthiazol-2yl)-2, 5-diphenyltetrazolium bromide; MyoD, myogenic differentiation; NAT, natural antisense transcript; NCBI, National Center for Biotechnology Information; ndsRNA, natural double-stranded RNA; NEAT1, nuclear enriched abundant transcript 1; Nlp, ninein-like protein; NORAD, noncoding RNA activated by DNA damage; OLA1, Obg-like ATPase 1; PANDA, P21-associated noncoding RNA DNA damage-activated; PCAT1, prostate cancer– associated transcript 1; PCR, polymerase chain reaction; PI, propidium iodide; pRb, phosphorylated retinoblastoma protein; PRC1/2, polycomb repressive complex 1/2; PTGS, posttranscriptional gene silencing; PVT1, plasmacytoma variant translocation 1; RAN, rasrelated nuclear protein; RBP, RNA-binding protein; RCC1, regulator of chromosome condensation 1; RIP, RNA-immunoprecipitation; RNA-seq, RNA sequencing; RNasin, RNase inhibitor; RoR, regulator of reprogramming; RPA, RNase protection assay; RT-PCR, reverse transcription PCR; shRNA, short hairpin RNA; SINEB2, short interspersed nuclear element B2; Sirt1-AS, Sirtuin 1 antisense RNA; snRNA, small nuclear RNA; TE, transposable element; TR, tandem repeat; TUG1, taurine up-regulated gene 1; UCA1, urothelial cancer associated 1; Uchl, ubiquitin carboxyterminal hydrolase L1; XEF, Xenopus elongation factor; Xist, X-inactive specific transcript
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