UNDERSTANDING THE RULES OF LIFE - Regulation of cellular stress responses by long noncoding RNAs

Human cells are constantly exposed to external and internal stressors causing damage to the cell and its genome. To cope with diverse environmental changes and ensure the survival of the organism, cells developed diverse stress adaptation strategies. Whereas cellular stress usually leads to programmed cell death in normal cells, cancer cells can by-pass growth-limiting checkpoints resulting in tumor cell survival.

Long noncoding RNAs (lncRNAs) have emerged as key regulators of diverse physiological and pathological processes including stress response. However, the molecular basis of the lncRNA-directed regulation of stress responses remains enigmatic in the majority of studied cases. The Shkumatava laboratory has recently identified a cancer-associated lncRNA that buffers cellular stress. Genetic inactivation of the lncRNA leads to constant upregulation of the p53 pathway, which acts as a cellular sensor of DNA damage and a guardian of the genome. We found that this lncRNA engages with key DNA damage proteins via its conserved RNA sequence motifs. Our goal is now to define the function of these deeply conserved RNA elements and reveal how their association with the DNA damage machinery contributes to regulation of the cellular stress response and maintenance of the cell integrity.

To achieve our goals, we employ state-of-the-art of technologies including genome editing in relevant mammalian cell lines, high resolution imaging, genome-wide sequencing approaches (RNA-seq, ChIP-seq, ATAC-seq), diverse cellular and molecular approaches including our novel high throughput incPRINT RNA-protein interaction technology. The student will develop specific skills in all mentioned above disciplines. The project will be jointly supervised by Dr Shkumatava who is an expert in RNA biology and Dr Buonomo who is an expert in genome stability and DNA damage response. In addition, we collaborate with bioinformaticians for data analyses.