Composition and function of telomeric multi-protein complexes and their regulation by ADP-ribosylation

端粒的维持对基因组的稳定性至关重要。Shelterin复合物由六种不同的蛋白质组成，保护端粒免受非法DNA损伤反应，并通过端粒酶协调端粒延伸。端粒保护和长度稳态的精确机制还不完全清楚。染色体末端与DNA损伤传感器隔离以避免致死染色体融合，同时需要暴露于端粒酶以进行端粒延伸，细胞如何解决这一难题？在人类细胞中，ADP核糖基转移酶端锚聚合酶修饰Shelterin，使端粒依赖性端粒延伸成为可能，这可能是通过调节Shelterin的化学计量。在本项目中，我们的目标是结合联合收割机生化，生物物理，单分子荧光和细胞为基础的研究，以了解的相关性和调节Shelterin复杂的化学计量端粒保护和长度稳态。

Telomere maintenance is vital to genome stability. The Shelterin complex, composed of six different proteins, protects telomeres from an illicit DNA damage response and orchestrates telomere extension by telomerase. The precise mechanisms of telomere protection and length homeostasis are incompletely understood. How does the cell navigate the dilemma that chromosome termini are sequestered from the DNA-damage sensing machinery to avoid lethalchromosome fusions whilst needing to be exposed to telomerase for telomere extension? In human cells, the ADPribosyltransferase tankyrase modifies Shelterin to enable telomerase-dependent telomere extension, presumably bymodulating Shelterin stoichiometry. In this project, we aim to combine biochemical, biophysical, single-molecule fluorescence and cell-based studies to understand the relevance and regulation of Shelterin complex stoichiometryin telomere protection and length homeostasis.