Biology subjects

Shkumatava, A.

Publications and source records attributed to Shkumatava, A..

5 recordsLinked to original sources

bioRxiv2025

The RNA-binding protein RSRC2 promotes mitotic fidelity by interacting with the lncRNA C1QTNF1-AS1

Mitotic fidelity depends on proper chromosome alignment at the spindle equator, a process known as chromosome congression, driven by well-established protein networks. Whereas RNA-binding proteins and noncoding RNAs have been implicated in cell division, their interplay during this process remains unknown. Here, we discover that RSRC2, an arginine/serine-rich RNA-binding protein, plays an essential role in cell division by interacting with the long non-coding RNA C1QTNF1-AS1. The loss of either RSRC2 or C1QTNF1-AS1 results in defects in chromosome congression and mitotic progression. We show that RSRC2 interacts with distinct sets of proteins involved in splicing and centrosome biogenesis, contributing to the fidelity of cell division through two different mechanisms: one linked to the splicing of mitotic regulators and the other by localising to mitotic centrosomes for which the interaction with the C1QTNF1-AS1 RNA is required. Our study uncovers RSRC2 as a new regulator of cell division and illustrates how RNA-protein complexes promote error-free mitosis.

cell biology↗

bioRxiv2024

Conserved RNA-binding protein interactions mediate syntologous lncRNA functions

Syntologous long noncoding RNAs (lncRNAs) are loci with conserved genomic positions that often show little or no sequence similarity. Despite diverging primary sequences, lncRNA syntologs from distant species can carry out similar functions. However, determinants underlying conserved functions of syntologous lncRNA transcripts with no sequence similarity remain unknown. Using CASC15 and melanoma formation as a paradigm for fast evolving lncRNAs and their functions, we found that human and zebrafish CASC15 syntologs with no detectable sequence similarity retained their function across 450 million years of evolution. Similar to the casc15-deficient zebrafish, CASC15-mutant human melanoma cells show increased cell migration. Expression of human CASC15 in zebrafish rescues loss of casc15 function by attenuating melanoma formation. This conserved function is supported by a set of RNA-binding proteins, interacting with both zebrafish and human CASC15 transcripts. Together, our findings demonstrate that conserved RNA-protein interactions can define functions of rapidly evolving lncRNA transcripts.

molecular biology↗

bioRxiv2023

The stress-induced lincRNA JUNI is a critical factor for cancer cell survival whose interactome is a prognostic signature in clear cell renal cell carcinoma

Cancer cells rely on adaptive mechanisms to survive the multiple stressors they encounter, including replication stress, toxic metabolic products and exposure to genotoxic drugs. Understanding the factors involved in these stress responses is crucial for developing effective treatments. Here, we describe a previously unstudied long non-coding RNA (lncRNA), JUNI (JUN-DT, LINC01135), which is regulated by MAPK and responsive to stress. JUNI positively regulates the expression of its neighboring gene JUN, a key transducer of signals that regulate multiple transcriptional outputs. Our findings reveal that silencing JUNI sensitizes cancer cells to chemotherapeutic drugs or UV radiation, and that its prolonged silencing leads to cell death regardless of stress exposure, highlighting the pro-survival importance of JUNI. We identified 57 proteins that interact with JUNI and found that the activity of one of them, the MAPK phosphatase and inhibitor DUSP14, is inhibited by JUNI. This effect results in c-Jun induction following exposure of cancer cells to UV radiation and promotes cellular survival. Although JUNI regulates c-Jun and its downstream targets, the pro-survival effects in cells not exposed to stress are only partially dependent on c-Jun regulation. JUNI expression levels significantly correlate with patients survival across 11 different types of cancer. Interestingly, the correlation of DUSP14 expression levels with patients survival in nine of these tumors is coherently inverse, indicating contradicting effects that are relevant not only for c-Jun induction and cellular survival but also in human cancer. Notably, we observed particularly significant antagonistic correlations in clear cell renal cell carcinoma (ccRCC) (p=5.7E-05 for JUNI and p=2.9E- 05 for Dusp14). In fact, the expression levels of 76% of JUNI-interacting proteins predict the prognosis of ccRCC patients significantly. Furthermore, a combined hazard ratio calculation demonstrates that this gene combination serves as a highly specific prognostic signature for ccRCC. Overall, our findings reveal a new important factor in stress signaling and cellular survival that is involved in ccRCC.

cell biology↗

bioRxiv2023

adgrl3.1-deficient zebrafish show noradrenaline-mediated externalizing behaviors, and altered expression of externalizing disorder-candidate genes, suggesting functional targets for treatment

Externalising disorders (ED) are a cause of concern for public health, and their high heritability make genetic risk factors a priority for research. Adhesion G Protein-Coupled Receptor L3 (ADGRL3) is strongly linked to several EDs, and loss-of-function models have shown impacts of this gene on several core ED-related behaviors. For example, adgrl3.1-/- zebrafish show high levels of hyperactivity. However, our understanding of the mechanisms by which this gene influences behavior is incomplete. Here we characterized, for the first time, externalizing behavioral phenotypes of adgrl3.1-/- zebrafish and found them to be highly impulsive, show boldness in a novel environment, have attentional deficits, and show high levels of hyperactivity. All of these phenotypes were rescued by atomoxetine, demonstrating noradrenergic mediation of the externalizing effects of adgrl3.1. Transcriptomic analyses of the brains of adgrl3.1-/- vs wild type fish revealed several differentially expressed genes and enriched gene clusters that were independent of noradrenergic manipulation. This suggests new putative functional pathways underlying ED-related behaviors, and potential targets for the treatment of ED.

neuroscience↗

bioRxiv2022

Cancer cells survival is dependent on the lincRNA JUNI

Identification of key factors for cellular survival is a basis for therapy. We identified JUNI (linc01135) as a stress-regulated lncRNA, essential for cell survival and implicated in cancer. Besides regulating c-Jun expression we demonstrate c-Jun-independent, robust requirement for cell survival. Analysis of median survival of cancer patients suffering from various types of cancer reveals correlations of JUNI expression levels with alterations in patients survival. JUNIs antagonistic interaction with DUSP14, a negative regulator of the JNK pathway, underlies the regulation of c-Jun and partial effects on cellular survival. Consistently, DUSP14 expression is coherently inversely-correlated with the survival of patients suffering from the same types of cancer. Our data suggests that JUNI is a novel master regulator of cell fate. SummaryJUNI is a novel regulator of cell survival, JNK activation and c-Jun expression, implicated in survival of cancer patients

cell biology↗