Mechanism of end protection in stem cells

干细胞末端保护机制

基本信息

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
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

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，它们会变得功能失调，并引起染色体末端的DNA损伤响应途径的激活。端粒功能失调的细胞可以经历编程的细胞死亡，进入不可逆的细胞周期停滞，或累积基因组不稳定性，并最终转化为侵略性的癌细胞。使用庇护素成分的条件缺失，我们表明分化状态对端粒功能障碍的细胞反应有重大影响（Lazzerini Denchi等，2006; Lobanova et al。，2017; Pinzaru等，2016）。我们已经证明，为了响应相同类型的遗传操作，某些细胞类型会累积基因组不稳定性，并最终发展为侵袭性肿瘤。相比之下，其他人从未克服端粒功能障碍施加的扩散障碍（Lobanova等，2017； Pinzaru等，2016）。鉴于端粒驱动的基因组不稳定性在癌症的发展中的重要性，这些数据突出了关键肿瘤发射过程中知识的显着差距。我们正在进行的旨在了解端粒功能障碍与分化状态之间的联系的工作表明，在没有必要的庇护所成分的情况下，多能多能的胚胎干细胞（ESC）可以生存。这一意外发现为多能干细胞中端粒保护机制开辟了一系列出色的问题