Noncoding RNA Ginir functions as an oncogene by associating with centrosomal proteins

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.

Mechanisms and consequences of subcellular RNA localization across diverse cell types

“…In Melanoma, cytoplasmic and mitochondrial localization of long noncoding RNA SAMMSON has been shown to increase clonogenic potential, and knock‐down of SAMMSON decreases melanoma viability 168 . Additionally, the noncoding RNA GINIR associates with centrosomal proteins, with over‐expression resulting in disruption of Brca1 protein activity and more aggressive tumors 169 …”

The Emerging Role of ncRNAs and RNA-Binding Proteins in Mitotic Apparatus Formation

“…Three years later, similar results were found in mammalian centrosomes purified from mitotic Ptk2 cells [18]. However, although several studies have revealed the sequence of RNAs localized in the centrosome of the surf clam and mouse [19,20], the critical RNAs responsible for microtubule nucleation in the centrosome have not been identified. The function of ncRNAs transcribed from the centromere region (centromeric RNAs) at the kinetochore has been studied since 2004 and 2007 with maize and human cells, respectively [21,22] Centromeric RNAs are associated with critical kinetochore proteins, recruiting and regulating them at the kinetochore [23].…”

“…Regarding vertebrates, genomic-instability-inducing RNA (Ginir), a mammalian lncRNA conserved in rodents potentially involved in centrosome function, was identified as an oncogene in mouse melanoma cells [20]. The Ginir locus is also transcribed as a completely overlapping antisense to Ginir (Giniras).…”

“…Cep112 interacts with breast cancer type 1 susceptibility protein (Brca1), another centrosome-associated protein. The interaction of the Cep112 protein and Brca1 protein is impaired when cells show elevated levels of Ginir RNA, resulting in severe dysregulation and abnormality in mitosis, leading to malignant transformation [20]. In contrast to Ginir, Giniras does not function as a dominant oncogene in mouse cells but rather when expressed in combination with Ginir, it suppresses its oncogenic function.…”

Long noncoding RNA DPP10-AS1 promotes malignant processes through epigenetically activating its cognate gene DPP10 to predict poor prognosis in lung cancer patients

“…Notably, these lncRNAs have key roles in gene regulation and thus affect various aspects of cellular behaviors, including differentiation, proliferation, invasion, migration or genomic stability [40]. In addition, the highly expressed lncRNAs function as oncogenes to activate oncogenic signal pathways and promote the carcinogenesis [41][42][43]. Importantly, the potential values of lncRNAs in cancer diagnosis, prognosis and targeted therapy has been also shown [14,44,45].…”