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至关重要。这种保护素复合体由六种不同的蛋白质组成，保护端粒免受非法DNA损伤反应的影响，并通过端粒酶协调端粒的延伸。端粒保护和长度稳态的确切机制还不完全清楚。细胞如何应对染色体末端从DNA损伤传感机制中分离出来的两难境地，以避免淋巴细胞染色体融合，同时需要暴露在端粒酶中以延长端粒？在人类细胞中，腺苷二磷酸转移酶Tankyrase可以通过调节谢尔特林的化学计量比来修饰端粒酶依赖的端粒延伸。在这个项目中，我们的目标是结合生化、生物物理、单分子荧光和基于细胞的研究来了解保护素复合体化学计量与端粒保护和长度动态平衡的相关性和调节。

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.