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

了解生命规则 - 长非编码 RNA 调节细胞应激反应

• 批准号: 2890784
• 金额: --
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2890784
• 关键词: UNDERSTANDING; RULES; LIFE; Regulation; cellular

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.

人类细胞不断暴露于外部和内部压力源，对细胞及其基因组造成损害。为了科普不同的环境变化，确保生物体的生存，细胞发展了不同的压力适应策略。尽管细胞应激通常导致正常细胞中的程序性细胞死亡，但癌细胞可以绕过生长限制检查点，从而导致肿瘤细胞存活。长链非编码RNA（lncRNA）已成为包括应激反应在内的多种生理和病理过程的关键调节因子。然而，在大多数研究病例中，lncRNA指导的应激反应调节的分子基础仍然是谜。Shkirava实验室最近发现了一种与癌症相关的lncRNA，可以缓冲细胞应激。lncRNA的遗传失活导致p53途径的持续上调，p53途径充当DNA损伤的细胞传感器和基因组的监护人。我们发现这种lncRNA通过其保守的RNA序列基序与关键的DNA损伤蛋白结合。我们现在的目标是确定这些高度保守的RNA元件的功能，并揭示它们与DNA损伤机制的关联如何有助于调节细胞应激反应和维持细胞完整性。为了实现我们的目标，我们采用了最先进的技术，包括相关哺乳动物细胞系中的基因组编辑，高分辨率成像，全基因组测序方法（RNA-seq，ChIP-seq，ATAC-seq），多种细胞和分子方法，包括我们的新型高通量incPRINT RNA-蛋白质相互作用技术。学生将在所有上述学科发展的具体技能。该项目将由RNA生物学专家Shkanova博士和基因组稳定性和DNA损伤反应专家Buonomo博士共同监督。此外，我们还与生物信息学家合作进行数据分析。