Mechanism of end protection in stem cells

干细胞末端保护机制

• 批准号: 10926453
• 负责人: Eros Lazzerini Denchi
• 金额: $ 71.42万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10926453
• 关键词: Apoptosis; Cell Cycle Arrest; Cells; Chromosomes; DNA Damage; Data; Defect; Development; Functional disorder; Genomic Instability; Goals; Knowledge; Malignant Neoplasms; Pathway interactions; Pluripotent Stem Cells; Process; Proliferating; Research Project Grants; Work; cancer cell; cell type; embryonic stem cell; genetic manipulation; response; stem cells; telomere; tumor; tumor initiation

When telomeres become critically short, they become dysfunctional and elicit activation of the DNA damage response pathway at chromosome ends. Cells with dysfunctional telomeres can either undergo programmed cell death, enter into an irreversible cell cycle arrest, or accumulate genome instability and eventually transform into an aggressive cancer cell. Using conditional deletion of shelterin components, we have shown that the differentiation status has a major impact on the cellular response to telomere dysfunction (Lazzerini Denchi et al., 2006; Lobanova et al., 2017; Pinzaru et al., 2016). We have demonstrated that, in response to the same type of genetic manipulation, certain cell types accumulate genome instability and eventually develop into aggressive tumors. In contrast, others never overcome the proliferation barrier imposed by telomere dysfunction (Lobanova et al., 2017; Pinzaru et al., 2016). Given the importance of telomere-driven genome instability in the development of cancer, these data highlight a significant gap in knowledge in a critical tumor-initiating process. Our ongoing work aimed at understanding the connection between telomere dysfunction and the differentiation status revealed that, unexpectantly, pluripotent embryonic stem cells (ESCs) could survive in the absence of essential shelterin components. This unexpected finding opens a set of outstanding questions regarding the mechanism of telomere protection in pluripotent stem cells

当端粒变得非常短时，它们变得功能失调并引发染色体末端DNA损伤反应途径的激活。端粒功能障碍的细胞可以经历程序性细胞死亡，进入不可逆的细胞周期停滞，或积累基因组不稳定性并最终转化为侵袭性癌细胞。使用shelterin组分的条件性缺失，我们已经表明分化状态对端粒功能障碍的细胞应答具有主要影响（Lazzerini Denchi等人，2006; Lobanova等人，2017; Pinzaru等人，2016年）。我们已经证明，响应于相同类型的遗传操作，某些细胞类型积累了基因组不稳定性，并最终发展成侵袭性肿瘤。相比之下，其他人从未克服端粒功能障碍所施加的增殖屏障（Lobanova et al.，2017; Pinzaru等人，2016年）。鉴于端粒驱动的基因组不稳定性在癌症发展中的重要性，这些数据突出了在关键的肿瘤启动过程中的知识差距。我们正在进行的工作旨在了解端粒功能障碍和分化状态之间的联系，意外地，多能胚胎干细胞（ESCs）可以在缺乏必要的shelterin成分的情况下存活。这一意外发现开启了一系列关于多能干细胞端粒保护机制的悬而未决的问题